Nile gaxostat treatments

Abstract

The present disclosure relates to improved methods of treatment of nirogastat. The invention also includes improved methods of treating conditions responsive to inhibition of gamma secretase, such as sclerofibroma, multiple myeloma, ovarian granulocytoma, with nirogastat and pharmaceutically acceptable salts thereof.

Description

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 365,125, filed May 20, 2022, and U.S. Provisional Application No. 63 / 365,193, filed May 23, 2022, each of which is hereby incorporated by reference. Technical Field

[0002] This disclosure relates to an improved treatment for nirogacestat. Background Technology

[0003] (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphth-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propyl-2-yl)-1H-imidazol-4-yl)pentanamide (“nilogasstat” or the following compound of formula (I)) is a γ-secretase inhibitor that inhibits the production of Aβ-peptide.

[0004]

[0005] Desmoidomas (also known as invasive fibromatosis) are rare, locally invasive, slow-growing soft tissue tumors. According to the World Health Organization, a desmoidoma is defined as a clonal proliferation of fibroblasts occurring in deep soft tissues and characterized by invasive growth and a tendency for local recurrence, but not metastasis (Kasper et al., Oncologist, 2011, 16(5):682-93). Desmoidomas are considered benign; however, they cause significant incidence through infiltration or exerting a mass effect on important structures (Lewis et al., Ann Surg. 1999, 229(6):866-72; Smith et al., Br JSurg. 2000, 87(5):608-13). Desmoidomas comprise soft tissue masses occurring in any part of the body within various types of connective tissue, including muscles and fascia aponeurosis. Desmoid tumors infiltrate surrounding structures and spread along plains and muscles, which can lead to severe pain, functional impairment, and, more rarely, life-threatening conditions (Penel et al., Eur J Cancer. 2017, 83:125-31). Although desmoid tumors are benign in nature, they can be aggressive, resulting in a significant morbidity, with a high local recurrence rate (up to 60%) despite extensive resection (Penel, 2017).

[0006] Therefore, there is a need for compositions containing nirogasat or its pharmaceutically acceptable salts to treat patients with diseases or conditions suitable for treatment with gamma-secretase inhibitors. Summary of the Invention

[0007] The present invention includes an improved method for treating diseases responsive to inhibition of γ-secretase, such as desmoidoma, multiple myeloma, and ovarian granulosa cell tumor, with nilogasstat and its pharmaceutically acceptable salts.

[0008] One implementation method is a way of treating patients in need of a disease that responds to inhibition of γ-secretase (such as desmoidoma or multiple myeloma), comprising orally administering 150 mg (free base equivalent dose) of nirogalstat or a pharmaceutically acceptable salt thereof to the patient twice daily, wherein the method comprises one or more of the following:

[0009] (a) If a patient has grade 3 diarrhea that persists for at least 3 days after receiving maximal drug therapy, discontinue nirogalstat or its pharmaceutically acceptable salt until the diarrhea subsides to grade 1 diarrhea or baseline, and then resume oral administration of nirogalstat or its pharmaceutically acceptable salt at a dose of 100 mg (free base equivalent) twice daily.

[0010] (b) When a patient develops grade 3 folliculitis, discontinue nirogalstat or its pharmaceutically acceptable salt until the folliculitis resolves to no higher than grade 1 folliculitis or baseline, and then resume oral administration of nirogalstat or its pharmaceutically acceptable salt twice daily at a dose of 100 mg (free base equivalent).

[0011] (c) When a patient develops grade 3 maculopapular rash, discontinue nirogalstat or its pharmaceutically acceptable salt until the maculopapular rash subsides to no higher than grade 1 maculopapular rash or baseline, and then resume oral administration of nirogalstat or its pharmaceutically acceptable salt twice daily at a dose of 100 mg (free base equivalent).

[0012] (d) When a patient develops grade 3 hidradenitis, discontinue nirogalstat or its pharmaceutically acceptable salt until the hidradenitis resolves to a level no higher than grade 1 hidradenitis or baseline, and then resume oral administration of nirogalstat or its pharmaceutically acceptable salt twice daily at a dose of 100 mg (free base equivalent).

[0013] (e) If a patient develops grade 3 hypophosphatemia that persists for at least 7 days after receiving maximum replacement therapy, discontinue nirogalstat or its pharmaceutically acceptable salt until the hypophosphatemia resolves to no higher than grade 1 hypophosphatemia or baseline, and then resume oral administration of nirogalstat or its pharmaceutically acceptable salt at a dose of 100 mg twice daily (free base equivalent).

[0014] (f) If a patient develops grade 3 hypokalemia despite receiving maximal replacement therapy, discontinue nirogalstat or its pharmaceutically acceptable salts until the hypokalemia resolves to a level not exceeding grade 1 hypokalemia or baseline, then resume oral administration of nirogalstat or its pharmaceutically acceptable salts at a dose of 100 mg twice daily (free base equivalent); and

[0015] (g) If a patient has alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels that are 3 to 5 times the upper limit of normal (ULN), discontinue nirogalstat or its pharmaceutically acceptable salts until ALT, AST, or both subside to no more than 3 times the ULN or baseline, and then resume oral administration of nirogalstat or its pharmaceutically acceptable salts twice daily at a dose of 100 mg (free base equivalent).

[0016] In one implementation, the method further includes one or more of the following:

[0017] (h) When a patient has ALT or AST greater than 5 times the ULN, permanently discontinue treatment with nirogasat or its pharmaceutically acceptable salts.

[0018] (i) Permanently discontinue treatment with nirogasat or its pharmaceutically acceptable salts when the patient experiences anaphylactic shock or other severe hypersensitivity reactions; and

[0019] (j) In the event of another serious or life-threatening adverse reaction, discontinue nirogalstat or its pharmaceutically acceptable salt until the adverse reaction resolves to a grade 1 or lower than baseline, and then, after careful consideration of the potential benefits and the likelihood of recurrence of the adverse reaction, (A) restart oral administration of nirogalstat or its pharmaceutically acceptable salt at a dose of 100 mg twice daily (free base equivalent), and (B) permanently discontinue treatment with nirogalstat or its pharmaceutically acceptable salt if a serious or life-threatening adverse reaction recurs at a dose of 100 mg twice daily (free base equivalent).

[0020] In another embodiment, the method includes (a) when a patient has grade 3 diarrhea that persists for at least 3 days after receiving maximal drug therapy, suspending the use of nirogalstat or its pharmaceutically acceptable salt until the diarrhea subsides to a level no higher than grade 1 diarrhea or baseline, and then resuming oral administration of nirogalstat or its pharmaceutically acceptable salt at a dose of 100 mg (free base equivalent) twice daily.

[0021] In yet another implementation, the method includes (b) when a patient develops grade 3 folliculitis, suspending the use of nirogalstat or a pharmaceutically acceptable salt thereof until the folliculitis resolves to no higher than grade 1 folliculitis or baseline, and then resuming oral administration of nirogalstat or a pharmaceutically acceptable salt thereof twice daily at a dose of 100 mg (free base equivalent dose).

[0022] In yet another implementation, the method includes (c) when a patient develops grade 3 maculopapular rash, suspending the use of nirogalstat or a pharmaceutically acceptable salt thereof until the maculopapular rash subsides to no higher than grade 1 maculopapular rash or baseline, and then resuming oral administration of nirogalstat or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent) twice daily.

[0023] In yet another implementation, the method includes (d) when a patient develops grade 3 hidradenitis, suspending the use of nirogalstat or a pharmaceutically acceptable salt thereof until the hidradenitis subsides to no higher than grade 1 hidradenitis or baseline, and then resuming oral administration of nirogalstat or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent) twice daily.

[0024] In yet another implementation, the method includes (e) when a patient has grade 3 hypophosphatemia that persists for at least 7 days after receiving maximal replacement therapy, suspending the use of nirogalstat or its pharmaceutically acceptable salt until the hypophosphatemia resolves to no higher than grade 1 hypophosphatemia or baseline, and then resuming oral administration of nirogalstat or its pharmaceutically acceptable salt at a dose of 100 mg (free base equivalent) twice daily.

[0025] In yet another implementation, the method includes (f) when a patient still has grade 3 hypokalemia after receiving maximal replacement therapy, suspending the use of nirogalstat or its pharmaceutically acceptable salt until the hypokalemia resolves to no higher than grade 1 hypokalemia or baseline, and then resuming oral administration of nirogalstat or its pharmaceutically acceptable salt at a dose of 100 mg (free base equivalent) twice daily.

[0026] In yet another implementation, the method includes (g) when a patient has ALT or AST levels 3 to 5 times the ULN, suspending the use of nirogalstat or a pharmaceutically acceptable salt thereof until ALT, AST, or both subside to no more than 3 times the ULN or baseline, and then resuming oral administration of nirogalstat or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent) twice daily.

[0027] In yet another implementation, the method includes (h) permanently terminating treatment with nirogasat or a pharmaceutically acceptable salt thereof when the patient presents with ALT or AST greater than 5 times the ULN.

[0028] In yet another implementation, the method includes (i) permanently terminating treatment with nirogasat or a pharmaceutically acceptable salt thereof when the patient experiences anaphylactic shock or other severe hypersensitivity reactions.

[0029] In yet another implementation, the method includes:

[0030] (a) If a patient has grade 3 diarrhea that persists for at least 3 days after receiving maximal drug therapy, discontinue nirogalstat or its pharmaceutically acceptable salt until the diarrhea subsides to grade 1 diarrhea or baseline, and then resume oral administration of nirogalstat or its pharmaceutically acceptable salt at a dose of 100 mg (free base equivalent) twice daily.

[0031] (b) When a patient develops grade 3 folliculitis, discontinue nirogalstat or its pharmaceutically acceptable salt until the folliculitis resolves to no higher than grade 1 folliculitis or baseline, and then resume oral administration of nirogalstat or its pharmaceutically acceptable salt twice daily at a dose of 100 mg (free base equivalent).

[0032] (c) When a patient develops grade 3 maculopapular rash, discontinue nirogalstat or its pharmaceutically acceptable salt until the maculopapular rash subsides to no higher than grade 1 maculopapular rash or baseline, and then resume oral administration of nirogalstat or its pharmaceutically acceptable salt twice daily at a dose of 100 mg (free base equivalent).

[0033] (d) When a patient develops grade 3 hidradenitis, discontinue nirogalstat or its pharmaceutically acceptable salt until the hidradenitis resolves to a level no higher than grade 1 hidradenitis or baseline, and then resume oral administration of nirogalstat or its pharmaceutically acceptable salt twice daily at a dose of 100 mg (free base equivalent).

[0034] (e) If a patient develops grade 3 hypophosphatemia that persists for at least 7 days after receiving maximum replacement therapy, discontinue nirogalstat or its pharmaceutically acceptable salt until the hypophosphatemia resolves to no higher than grade 1 hypophosphatemia or baseline, and then resume oral administration of nirogalstat or its pharmaceutically acceptable salt at a dose of 100 mg twice daily (free base equivalent).

[0035] (f) If a patient develops grade 3 hypokalemia despite receiving maximal replacement therapy, discontinue nirogalstat or its pharmaceutically acceptable salts until the hypokalemia resolves to a level not exceeding grade 1 hypokalemia or baseline, then resume oral administration of nirogalstat or its pharmaceutically acceptable salts at a dose of 100 mg twice daily (free base equivalent); and

[0036] (g) When a patient has ALT or AST that is 3 to 5 times the ULN, discontinue nirogalstat or its pharmaceutically acceptable salt until ALT, AST or both have subsided to no more than 3 times the ULN or baseline, and then resume oral administration of nirogalstat or its pharmaceutically acceptable salt twice daily at a dose of 100 mg (free base equivalent).

[0037] In yet another implementation, the method includes:

[0038] (a) If a patient has grade 3 diarrhea that persists for at least 3 days after receiving maximal drug therapy, discontinue nirogalstat or its pharmaceutically acceptable salt until the diarrhea subsides to grade 1 diarrhea or baseline, and then resume oral administration of nirogalstat or its pharmaceutically acceptable salt at a dose of 100 mg (free base equivalent) twice daily.

[0039] (b) When a patient develops grade 3 folliculitis, discontinue nirogalstat or its pharmaceutically acceptable salt until the folliculitis resolves to no higher than grade 1 folliculitis or baseline, and then resume oral administration of nirogalstat or its pharmaceutically acceptable salt twice daily at a dose of 100 mg (free base equivalent).

[0040] (c) When a patient develops grade 3 maculopapular rash, discontinue nirogalstat or its pharmaceutically acceptable salt until the maculopapular rash subsides to no higher than grade 1 maculopapular rash or baseline, and then resume oral administration of nirogalstat or its pharmaceutically acceptable salt twice daily at a dose of 100 mg (free base equivalent).

[0041] (d) When a patient develops grade 3 hidradenitis, discontinue nirogalstat or its pharmaceutically acceptable salt until the hidradenitis resolves to a level no higher than grade 1 hidradenitis or baseline, and then resume oral administration of nirogalstat or its pharmaceutically acceptable salt twice daily at a dose of 100 mg (free base equivalent).

[0042] (e) If a patient develops grade 3 hypophosphatemia that persists for at least 7 days after receiving maximum replacement therapy, discontinue nirogalstat or its pharmaceutically acceptable salt until the hypophosphatemia resolves to no higher than grade 1 hypophosphatemia or baseline, and then resume oral administration of nirogalstat or its pharmaceutically acceptable salt at a dose of 100 mg twice daily (free base equivalent).

[0043] (f) If a patient develops grade 3 hypokalemia despite receiving maximum replacement therapy, discontinue nirogalstat or its pharmaceutically acceptable salts until the hypokalemia resolves to no higher than grade 1 hypokalemia or baseline, and then resume oral administration of nirogalstat or its pharmaceutically acceptable salts twice daily at a dose of 100 mg (free base equivalent).

[0044] (g) When a patient has ALT or AST that is 3 to 5 times the ULN, discontinue nirogalstat or its pharmaceutically acceptable salt until ALT, AST or both have subsided to no more than 3 times the ULN or baseline, and then resume oral administration of nirogalstat or its pharmaceutically acceptable salt twice daily at a dose of 100 mg (free base equivalent).

[0045] (h) When a patient has ALT or AST greater than 5 times the ULN, permanently discontinue treatment with nirogasat or its pharmaceutically acceptable salts.

[0046] (i) Permanently discontinue treatment with nirogasat or its pharmaceutically acceptable salts when the patient experiences anaphylactic shock or other severe hypersensitivity reactions; and

[0047] (j) In the event of another serious or life-threatening adverse reaction, discontinue nirogalstat or its pharmaceutically acceptable salt until the adverse reaction resolves to a grade 1 or lower than baseline, and then, after careful consideration of the potential benefits and the likelihood of recurrence of the adverse reaction, (A) restart oral administration of nirogalstat or its pharmaceutically acceptable salt at a dose of 100 mg twice daily (free base equivalent), and (B) permanently discontinue treatment with nirogalstat or its pharmaceutically acceptable salt if a serious or life-threatening adverse reaction recurs at a dose of 100 mg twice daily (free base equivalent).

[0048] In another implementation, when a patient experiences a grade 3 dermatological reaction, nirogalstat or its pharmaceutically acceptable salts are discontinued until the dermatological reaction subsides to a level no higher than a grade 1 dermatological reaction or baseline, and then nirogalstat or its pharmaceutically acceptable salts are restarted orally twice daily at a dose of 100 mg (free base equivalent).

[0049] In yet another implementation of any of the methods described herein, the patient has a mutation in the tumor suppressor gene for adenomatous polyposis (APC).

[0050] In yet another implementation of any of the methods described herein, the patient has a mutation in the CTNNB1 (β-catenin) gene.

[0051] In yet another embodiment of any of the methods described herein, the patient has previously received treatment with one or more tyrosine kinase inhibitors, such as sorafenib, pazopanib, sunitinib, imatinib, dasatinib, nilotinib, bosutinib, aciminib, and panatinib.

[0052] In yet another implementation of any of the methods described herein, the patient has an intra-abdominal tumor.

[0053] In yet another implementation of any of the methods described herein, the patient is an adult.

[0054] In yet another implementation of any of the methods described herein, the patient has a family history of familial adenomatous polyposis.

[0055] In yet another implementation of any of the methods described herein, the patient has a refractory or recurrent disease following prior treatment.

[0056] In yet another implementation of any of the methods described herein, the patient is an untreated patient.

[0057] In yet another implementation of any of the methods described herein, the patient is a postmenopausal woman.

[0058] In yet another implementation of any of the methods described herein, the patient is a person (a male patient).

[0059] In yet another embodiment of any of the methods described herein, gastric acid inhibitors are avoided or administered 4 hours after administration of nilogasstat or its pharmaceutically acceptable salts.

[0060] Another implementation is a method for treating desmoidoma in patients with a family history of familial adenomatous polyposis, comprising orally administering 150 mg (free base equivalent dose) of nirogalstat or a pharmaceutically acceptable salt thereof to the patient twice daily.

[0061] Another implementation is a method for treating desmoidoma in untreated patients, which involves administering 150 mg (free base equivalent dose) of nirogalstat or a pharmaceutically acceptable salt thereof orally to the patient twice daily.

[0062] In yet another embodiment of any of the methods described herein, nilogasstat or a pharmaceutically acceptable salt thereof is nilogasstat dihydrobromide.

[0063] In yet another embodiment of any of the methods described herein, following an initial administration of 150 mg (free base equivalent) of nirogalstat or a pharmaceutically acceptable salt thereof, the patient exhibited nirogalstat C levels of approximately 480 to approximately 950 ng / mL. max .

[0064] In yet another embodiment of any of the methods described herein, following an initial administration of 150 mg (free base equivalent) of nirogalstat or a pharmaceutically acceptable salt thereof, the patient exhibited nirogalstat C levels of approximately 550 to approximately 1100 ng / mL. max .

[0065] In yet another embodiment of any of the methods described herein, following an initial administration of 150 mg (free base equivalent) of nirogalstat or a pharmaceutically acceptable salt thereof, the patient exhibited nirogalstat C levels of approximately 600 to approximately 800 ng / mL. max .

[0066] In yet another embodiment of any of the methods described herein, following an initial administration of 150 mg (free base equivalent) of nirogalstat or a pharmaceutically acceptable salt thereof, the patient exhibited an AUC of less than 4000 ng·h / mL for nirogalstat. last In one implementation, following an initial administration of 150 mg (free base equivalent) of nirogalstat or a pharmaceutically acceptable salt thereof, patients exhibited an AUC of less than 4000 ng·h / mL for nirogalstat. last and approximately 480 to approximately 950 ng / mL of nilogasstatin C max .

[0067] In yet another embodiment of any of the methods described herein, following an initial administration of 150 mg (free base equivalent) of nirogalstat or a pharmaceutically acceptable salt thereof, patients exhibited an AUC of approximately 2000 to approximately 4000 ng·h / mL for nirogalstat. last In one implementation, following an initial administration of 150 mg (free base equivalent) of nirogalstat or a pharmaceutically acceptable salt thereof, patients exhibited an AUC of approximately 2000 to approximately 4000 ng·h / mL for nirogalstat. last and approximately 480 to approximately 950 ng / mL of nilogasstatin C max .

[0068] In yet another embodiment of any of the methods described herein, following an initial administration of 150 mg (free base equivalent) of nirogalstat or a pharmaceutically acceptable salt thereof, the patient exhibited an AUC of less than 4000 ng·h / mL for nirogalstat. inf In one implementation, following an initial administration of 150 mg (free base equivalent) of nirogalstat or a pharmaceutically acceptable salt thereof, patients exhibited an AUC of less than 4000 ng·h / mL for nirogalstat. inf and approximately 480 to approximately 950 ng / mL of nilogasstatin C max .

[0069] In yet another embodiment of any of the methods described herein, following an initial administration of 150 mg (free base equivalent) of nirogalstat or a pharmaceutically acceptable salt thereof, patients exhibited an AUC of approximately 2000 to approximately 4000 ng·h / mL for nirogalstat. infIn one implementation, following an initial administration of 150 mg (free base equivalent) of nirogalstat or a pharmaceutically acceptable salt thereof, patients exhibited an AUC of approximately 2000 to approximately 4000 ng·h / mL for nirogalstat. inf and approximately 480 to approximately 950 ng / mL of nilogasstatin C max .

[0070] In yet another embodiment of any of the methods described herein, following an initial administration of 150 mg (free base equivalent) of nirogalstat or a pharmaceutically acceptable salt thereof, patients exhibited an AUC of approximately 2200 to approximately 4800 ng·h / mL for nirogalstat. inf .

[0071] In yet another embodiment of any of the methods described herein, following an initial administration of 150 mg (free base equivalent) of nirogalstat or a pharmaceutically acceptable salt thereof, patients exhibited an AUC of approximately 2200 to approximately 3300 ng·h / mL for nirogalstat. inf .

[0072] In yet another embodiment of any of the methods described herein, patients exhibited steady-state exposure of approximately 1000 to approximately 1500 ng / mL of nirostatin C upon administration of 150 mg (free base equivalent) of nirostatin or a pharmaceutically acceptable salt thereof twice daily. max .

[0073] In yet another embodiment of any of the methods described herein, patients exhibited niroxista C levels of approximately 1100 to approximately 1400 ng / mL upon steady-state exposure to 150 mg (free base equivalent) of niroxista twice daily or a pharmaceutically acceptable salt thereof. max .

[0074] In yet another embodiment of any of the methods described herein, patients with steady-state exposure to nirogalalstat or a pharmaceutically acceptable salt thereof, administered twice daily, showed an AUC of approximately 5000 to approximately 8000 ng·h / mL. tau .

[0075] In yet another embodiment of any of the methods described herein, patients exhibited a niroxista AUC of approximately 6000 to approximately 7000 ng·h / mL upon steady-state exposure to 150 mg (free base equivalent) of niroxista twice daily or a pharmaceutically acceptable salt thereof. tau .

[0076] In one embodiment of the above method, patients are treated with 100 mg (free base equivalent) nirogalstat or a pharmaceutically acceptable salt thereof twice daily, and in the event of specific adverse reactions, this is reduced to 50 mg (free base equivalent) nirogalstat or a pharmaceutically acceptable salt thereof twice daily instead of 100 mg twice daily.

[0077] This article describes compounds containing formula (I).

[0078]

[0079] Or a pharmaceutically acceptable salt composition thereof, wherein the composition provides a mean maximum plasma concentration of the drug greater than 100 ng / ml (C rax ).

[0080] In addition, this article describes methods for treating desmoidomas, which include administering an oral dosage form containing 50 mg of nirogasstat or a pharmaceutically acceptable salt thereof to patients in need.

[0081] Furthermore, this article describes methods for treating desmoidomas in patients in need, which involve administering to the patient an oral dose of 50 mg of nirogasstat or a pharmaceutically acceptable salt thereof, wherein the oral dose provides a mean maximum plasma concentration of the drug greater than 100 ng / ml (C0.05). max ).

[0082] In addition, methods for treating desmoidomas in patients in need include administering to the patient a 50 mg oral dose of nirogasstat or a pharmaceutically acceptable salt thereof, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of less than 700 ng·h / ml. inf ).

[0083] This article also discloses methods for treating desmoidoma, which include administering 300 mg / day of nirogalstat or a pharmaceutically acceptable salt thereof to patients in need.

[0084] Furthermore, this article discloses methods for treating desmoidomas in patients in need, including administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof to the patient, wherein the oral dose provides a mean maximum plasma concentration of the drug greater than 100 ng / ml (C0.05). max ).

[0085] This article also discloses methods for treating desmoidomas in patients in need, which involve administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of less than 700 ng·h / ml. inf ).

[0086] In addition, this article discloses methods for treating multiple myeloma, which include administering 200 mg / day of nirogasat or a pharmaceutically acceptable salt thereof to patients in need.

[0087] In addition, this article discloses a method for treating multiple myeloma, including administering 100 mg / day of nirogalstat or a pharmaceutically acceptable salt thereof to patients in need.

[0088] This article also discloses methods for treating multiple myeloma, which include administering 200 mg of nirogasstat or a pharmaceutically acceptable salt thereof to patients in need once daily.

[0089] In addition, methods for treating multiple myeloma include administering 150 mg (free base equivalent) of nirogasstat or a pharmaceutically acceptable salt thereof once daily to patients in need.

[0090] This article also discloses methods for treating multiple myeloma, which include administering 100 mg of nirogasat or a pharmaceutically acceptable salt thereof to patients in need once daily.

[0091] In addition, this article discloses a method for treating multiple myeloma, including administering 50 mg of nirogasat or a pharmaceutically acceptable salt thereof to patients in need once daily.

[0092] In addition, methods for treating multiple myeloma in patients in need include administering an oral dose of 50 mg of nirogasat or a pharmaceutically acceptable salt thereof to the patient, wherein the oral dose provides a mean maximum plasma concentration of the drug greater than 100 ng / ml (C0). max ).

[0093] In addition, methods for treating multiple myeloma in patients in need include administering an oral dose of 100 mg of nirogasat or a pharmaceutically acceptable salt thereof to the patient, wherein the oral dose provides a mean maximum plasma concentration of the drug greater than 225 ng / ml (C0.05). max ).

[0094] This article also discloses methods for treating multiple myeloma in patients in need, which involve administering an oral dose of 50 mg of nirogasstat or a pharmaceutically acceptable salt thereof to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of less than 700 ng·h / ml. inf ).

[0095] Additionally, this article discloses methods for treating multiple myeloma in patients in need, comprising administering to the patient an oral dose of 100 mg of nirogasstat or a pharmaceutically acceptable salt thereof, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of less than 3000 ng·h / ml. inf ).

[0096] This article also discloses methods for treating multiple myeloma in patients in need, including administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof to the patient, wherein the oral dose provides a mean maximum plasma concentration of the drug greater than 100 ng / ml (C0.05). max ).

[0097] Additionally, this article discloses methods for treating multiple myeloma in patients in need, including administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof to the patient, wherein the oral dose provides a mean maximum plasma concentration of the drug greater than 225 ng / ml (C0.05). max ).

[0098] Furthermore, this article discloses methods for treating multiple myeloma in patients in need, including administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of less than 700 ng·h / ml. inf ).

[0099] This article also discloses methods for treating multiple myeloma in patients in need, including administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of less than 3000 ng·h / ml. inf ).

[0100] In addition, this article discloses methods for treating multiple myeloma in patients in need, including administering a single oral dose of nirogasat or a pharmaceutically acceptable salt thereof as concomitant therapy for multiple myeloma.

[0101] This article also discloses methods for treating multiple myeloma in patients in need, including administering an oral dose of nirogasat or a pharmaceutically acceptable salt thereof in combination with belantamab (belantamabmafodotin).

[0102] Another implementation is a method for treating multiple myeloma in a patient in need, comprising administering to the patient simultaneously (i) nirogalstat or a pharmaceutically acceptable salt thereof and (ii) one or more other active ingredients for treating multiple myeloma (e.g., BCMA therapy (e.g., intravenous administration)), wherein the method comprises (A) administering to the patient orally twice daily 150 mg (free base equivalent dose) of nirogalstat or a pharmaceutically acceptable salt thereof and (B) one or more of the following:

[0103] (a) If a patient has grade 3 diarrhea that persists for at least 3 days after receiving maximal drug therapy, discontinue nirogalstat or its pharmaceutically acceptable salt until the diarrhea subsides to grade 1 diarrhea or baseline, and then resume oral administration of nirogalstat or its pharmaceutically acceptable salt at a dose of 100 mg (free base equivalent) twice daily.

[0104] (b) When a patient develops grade 3 folliculitis, discontinue nirogalstat or its pharmaceutically acceptable salt until the folliculitis resolves to no higher than grade 1 folliculitis or baseline, and then resume oral administration of nirogalstat or its pharmaceutically acceptable salt twice daily at a dose of 100 mg (free base equivalent).

[0105] (c) When a patient develops grade 3 maculopapular rash, discontinue nirogalstat or its pharmaceutically acceptable salt until the maculopapular rash subsides to no higher than grade 1 maculopapular rash or baseline, and then resume oral administration of nirogalstat or its pharmaceutically acceptable salt twice daily at a dose of 100 mg (free base equivalent).

[0106] (d) When a patient develops grade 3 hidradenitis, discontinue nirogalstat or its pharmaceutically acceptable salt until the hidradenitis resolves to a level no higher than grade 1 hidradenitis or baseline, and then resume oral administration of nirogalstat or its pharmaceutically acceptable salt twice daily at a dose of 100 mg (free base equivalent).

[0107] (e) If a patient develops grade 3 hypophosphatemia that persists for at least 7 days after receiving maximum replacement therapy, discontinue nirogalstat or its pharmaceutically acceptable salt until the hypophosphatemia resolves to no higher than grade 1 hypophosphatemia or baseline, and then resume oral administration of nirogalstat or its pharmaceutically acceptable salt at a dose of 100 mg twice daily (free base equivalent).

[0108] (f) If a patient develops grade 3 hypokalemia despite receiving maximal replacement therapy, discontinue nirogalstat or its pharmaceutically acceptable salts until the hypokalemia resolves to a level not exceeding grade 1 hypokalemia or baseline, then resume oral administration of nirogalstat or its pharmaceutically acceptable salts at a dose of 100 mg twice daily (free base equivalent); and

[0109] (g) When a patient presents with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels 3 to 5 times the upper limit of normal (ULN), discontinue nirogalstat or its pharmaceutically acceptable salt until ALT, AST, or both subside to no more than 3 times the ULN or baseline, then resume oral administration of nirogalstat or its pharmaceutically acceptable salt twice daily at a dose of 100 mg (free base equivalent). In a preferred embodiment, BCMA therapy is administered concurrently to the patient. In another embodiment, the method further includes one or more of the following: (h) permanently discontinuing treatment with nirogalstat or its pharmaceutically acceptable salt when the patient experiences ALT or AST greater than 5 times the ULN; (i) permanently discontinuing treatment with nirogalstat or its pharmaceutically acceptable salt when the patient experiences anaphylactic shock or other severe hypersensitivity reactions; and (j) suspending nirogalstat or its pharmaceutically acceptable salt in the event of another serious or life-threatening adverse reaction until the adverse reaction subsides to a grade 1 adverse reaction or baseline, and then, after careful consideration of the potential benefits and the likelihood of recurrence of the adverse reaction, (A) restarting oral administration of nirogalstat or its pharmaceutically acceptable salt at a dose of 100 mg twice daily (free base equivalent dose), and (B) permanently discontinuing treatment with nirogalstat or its pharmaceutically acceptable salt if a serious or life-threatening adverse reaction recurs at a dose of 100 mg twice daily (free base equivalent dose).

[0110] Another implementation is a method for treating multiple myeloma in a patient in need, comprising administering to the patient simultaneously (i) nirogalstat or a pharmaceutically acceptable salt thereof and (ii) one or more other active ingredients for treating multiple myeloma (e.g., BCMA therapy), wherein the method comprises (A) administering to the patient orally twice daily 100 mg (free base equivalent dose) of nirogalstat or a pharmaceutically acceptable salt thereof and (B) one or more of the following:

[0111] (a) If a patient has grade 3 diarrhea that persists for at least 3 days after receiving maximal drug therapy, discontinue nirogalstat or its pharmaceutically acceptable salt until the diarrhea subsides to grade 1 diarrhea or baseline, and then resume oral administration of nirogalstat or its pharmaceutically acceptable salt twice daily at a dose of 50 mg (free base equivalent).

[0112] (b) When a patient develops grade 3 folliculitis, discontinue nirogalstat or its pharmaceutically acceptable salt until the folliculitis resolves to no higher than grade 1 folliculitis or baseline, and then resume oral administration of nirogalstat or its pharmaceutically acceptable salt twice daily at a dose of 50 mg (free base equivalent).

[0113] (c) When a patient develops grade 3 maculopapular rash, discontinue nirogalstat or its pharmaceutically acceptable salt until the maculopapular rash subsides to no higher than grade 1 maculopapular rash or baseline, and then resume oral administration of nirogalstat or its pharmaceutically acceptable salt twice daily at a dose of 50 mg (free base equivalent).

[0114] (d) When a patient develops grade 3 hidradenitis, discontinue nirogalstat or its pharmaceutically acceptable salt until the hidradenitis resolves to no higher than grade 1 hidradenitis or baseline, and then resume oral administration of nirogalstat or its pharmaceutically acceptable salt twice daily at a dose of 50 mg (free base equivalent).

[0115] (e) If a patient develops grade 3 hypophosphatemia that persists for at least 7 days after receiving maximum replacement therapy, discontinue nirogalstat or its pharmaceutically acceptable salt until the hypophosphatemia resolves to no higher than grade 1 hypophosphatemia or baseline, and then resume oral administration of nirogalstat or its pharmaceutically acceptable salt twice daily at a dose of 50 mg (free base equivalent).

[0116] (f) If a patient develops grade 3 hypokalemia despite receiving maximal replacement therapy, discontinue nirogalstat or its pharmaceutically acceptable salts until the hypokalemia resolves to a level no higher than grade 1 hypokalemia or baseline, then resume oral administration of nirogalstat or its pharmaceutically acceptable salts twice daily at a dose of 50 mg (free base equivalent); and

[0117] (g) When a patient presents with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels 3 to 5 times the upper limit of normal (ULN), discontinue nirogalstat or its pharmaceutically acceptable salt until ALT, AST, or both subside to no more than 3 times the ULN or baseline, then resume oral administration of nirogalstat or its pharmaceutically acceptable salt twice daily at a dose of 50 mg (free base equivalent). In a preferred embodiment, BCMA therapy is concurrently administered to the patient. In another embodiment, the method further includes one or more of the following: (h) permanently discontinuing treatment with nirogalstat or its pharmaceutically acceptable salt when the patient experiences ALT or AST greater than 5 times the ULN; (i) permanently discontinuing treatment with nirogalstat or its pharmaceutically acceptable salt when the patient experiences anaphylactic shock or other severe hypersensitivity reactions; and (j) suspending nirogalstat or its pharmaceutically acceptable salt in the event of another serious or life-threatening adverse reaction until the adverse reaction subsides to a grade 1 adverse reaction or baseline, and then, after careful consideration of the potential benefits and the likelihood of recurrence of the adverse reaction, (A) restarting oral administration of nirogalstat or its pharmaceutically acceptable salt at a dose of 50 mg twice daily (free base equivalent dose), and (B) permanently discontinuing treatment with nirogalstat or its pharmaceutically acceptable salt if a serious or life-threatening adverse reaction recurs at a dose of 50 mg twice daily (free base equivalent dose).

[0118] In some respects, the pharmaceutically acceptable salt form of nirogasstat in the compositions, dosage forms, or treatments described herein is the hydrobromide form. In some respects, the hydrobromide form is the dihydrobromide form.

[0119] In some respects, the composition or dose is administered orally to a person. In some respects, the composition or dose is in solid form. In some respects, the composition or dose is in the form of tablets or capsules.

[0120] In yet another embodiment of any of the methods described herein, one or more antiemetics and / or one or more antidiarrheals may be administered to the patient while being treated with nirogastart. Attached Figure Description

[0121] Figure 1 This is the protocol used in a phase 3 clinical trial of nirogabate dihydrobromide for the treatment of desmoidoma.

[0122] Figure 2 This is a protocol from a phase 3 clinical trial for the treatment of adult patients with desmoid tumors accompanied by uncontrollable pain.

[0123] Figure 3 Kaplan-Mayer plots of progression-free survival from randomization (ITT population) are provided.

[0124] Figure 4 This is a waterfall plot of the lowest percentage change in tumor size relative to baseline, according to RECIST 1.1 (ITT population).

[0125] Figure 5 This is a waterfall plot of the lowest percentage change in tumor size relative to baseline, according to RECIST 1.1 (ITT population).

[0126] Figure 6 This refers to the change in BPI SF API score relative to baseline (most severe pain in the past 24 hours) (ITT group).

[0127] Figure 7 This refers to the change in the total DTSS symptom score relative to baseline (ITT population).

[0128] Figure 8 This refers to the change in DTIS physical function domain scores relative to baseline (ITT group).

[0129] Figure 9 This is a flowchart illustrating the criteria for terminating a participant's participation due to hepatotoxicity in the clinical trial described in Example 2. Detailed Implementation

[0130] I. definition

[0131] To facilitate understanding of the disclosures described herein, several terms are defined below.

[0132] Generally, the nomenclature used herein and the laboratory procedures described herein in organic chemistry, medicinal chemistry, and pharmacology are those well-known and commonly used in the art. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0133] In this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural references unless the context clearly indicates otherwise. The terms “a” (or “an”) and “one or more” and “at least one” are used interchangeably herein. In some respects, the terms “a” or “an” mean “single”. In other respects, the terms “a” or “an” include “two or more” or “multiple”.

[0134] Furthermore, when used herein, “and / or” should be considered as a specific disclosure of each of the two specified features or components, whether together or apart from the other. Therefore, the term “and / or” as used herein in phrases such as “A and / or B” means to include: “A and B”; “A or B”; “A” (alone); and “B” (alone). Similarly, the term “and / or” as used in phrases such as “A, B and / or C” is intended to cover each of the following: A, B and C; A, B or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0135] The term "nirogalstat" refers to the single enantiomer (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthyl-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propyl-2-yl)-1H-imidazol-4-yl)pentanamide. The preferred pharmaceutically acceptable salt of nirogalstat is nirogalstat dihydrobromide (also known as nirogalstat hydrobromide). All amounts of nirogalstat or its salts used for administration are based on its free base. For example, 150 mg of nirogalstat dihydrobromide refers to the amount of nirogalstat dihydrobromide equivalent to 150 mg of nirogalstat free base (i.e., approximately 199.6 mg of nirogalstat dihydrobromide).

[0136] The term "subject" refers to an animal, including but not limited to primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, or mice. The terms "subject" and "patient" are used interchangeably herein to refer to, for example, mammalian subjects, such as human subjects.

[0137] As used herein, the terms “treat,” “treated,” and “treating” refer both to therapeutic treatment and preventative or preventative measures aimed at preventing or alleviating (reducing) an undesirable physical ailment, condition, or disease, or to achieving a beneficial or desired clinical outcome. Therefore, patients requiring treatment include those already diagnosed with or suspected of having the condition. Beneficial or desired clinical outcomes include, but are not limited to, symptom relief; reduction in the severity of the ailment, condition, or disease; stabilization of the condition, condition, or disease (i.e., no worsening); delay or slowing of the onset of the ailment, condition, or disease; improvement or remission of the condition, condition, or disease (whether partial or complete), whether detectable or undetectable; improvement in at least one measurable physical parameter, which may not necessarily be identifiable to the patient; or enhancement or improvement of the ailment, condition, or disease. Treatment includes eliciting a clinically significant response without excessive side effects. Treatment also includes extending survival compared to the expected survival without treatment. The term "therapeutic effective amount" refers to an amount of compound, when applied, sufficient to prevent the development of one or more symptoms of the treated condition, disease, or disorder, or to alleviate, to some extent, one or more symptoms of the treated condition, disease, or disorder. The term "therapeutic effective amount" also refers to an amount of compound sufficient to cause a biological or medical remission in cells, tissues, systems, animals, or humans that is sought by researchers, veterinarians, physicians, or clinicians.

[0138] In some respects, the method according to the invention is considered to have successfully “treated” a subject’s cancer, for example, multiple myeloma, if the patient exhibits one or more of the following: a reduction or complete absence of cancer cells; remission of one or more symptoms associated with the specific cancer; a reduction in morbidity and mortality; an improvement in quality of life; an increase in progression-free survival (“PFS”), disease-free survival (“DFS”), overall survival (“OS”), metastasis-free survival (“MFS”), complete response (“CR”), minimal residual disease (“MRD”), partial response (“PR”), stable disease (“SD”), reduced disease progression (“PD”), increased time to progression (“TTP”), or any combination thereof. In some respects, nationally or internationally accepted criteria for treatment outcomes for a given cancer can be used to determine whether a therapeutically effective amount of nilogasstat or a pharmaceutically acceptable salt thereof meets any of these specific endpoints (e.g., CR, PFS, PR).

[0139] The terms “pharmaceutically acceptable carrier,” “pharmaceuticalally acceptable excipient,” “physiologically acceptable carrier,” or “physiologically acceptable excipient” refer to pharmaceutically acceptable materials, compositions, or media, such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials. In one embodiment, each component is “pharmaceutically acceptable” in the sense of compatibility with other components of the pharmaceutical preparation and is suitable for contact with human or animal tissues or organs without excessive toxicity, irritation, allergic reactions, immunogenicity, or other problems or complications, in proportion to a reasonable benefit / risk ratio. See Remington: The Science and Practice of Pharmacy, 21st ed., Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 5th ed., Rowe et al., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and Handbook of Pharmaceutical Additives, 3rd ed., Ash and Ash, Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, Gibson, ed., CRC Press LLC: Boca Raton, FL, 2004 (incorporated hereby).

[0140] The term "pharmaceutically acceptable salt" refers to a relatively non-toxic inorganic or organic acid addition salt of compound A or compound B. These salts can be prepared in situ during the manufacture of the administration medium or dosage form, or by reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, followed by separation of the resulting salt during subsequent purification. Representative salts include hydrobromide, hydrochloride, sulfate, hydrogen sulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthalate, methanesulfonate, gluconate, lactobionate, and laurylsulfonate, etc. (See, for example, Berge et al. (1977), "Pharmaceutical Salts", J. Pharm. Sci. 66: 1-19).

[0141] Pharmaceutically acceptable salts of the compounds of this invention include conventional non-toxic salts or quaternary ammonium salts of the compounds, such as salts derived from non-toxic organic or inorganic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, aminosulfonic acid, phosphoric acid, nitric acid, etc.; and salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isothiosulfonic acid, etc.

[0142] In some respects, the compounds of the present invention may contain one or more acidic functional groups and are therefore capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. In these cases, the term "pharmaceutically acceptable salt" refers to a relatively non-toxic inorganic and organic base addition salt of the compounds of the present invention. These salts may also be prepared in situ during the manufacture of the administration medium or dosage form, or by reacting a purified compound in its free acid form with one of the following alone: ​​a suitable base, such as a hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation; ammonia; or a pharmaceutically acceptable primary, secondary, or tertiary organic amine. Representative alkali metal or alkaline earth metal salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts, etc. Representative organic amines used to form base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, etc. (See, for example, Berge et al., ibid.).

[0143] The term "intra-abdominal tumor" includes patients who have intra-abdominal tumors (including, for example, tumors in the mesentery or pelvis), as well as patients who have multiple target tumors located in both intra-abdominal and extra-abdominal locations.

[0144] The term "baseline" refers to an initial measurement of a disease taken at an earlier point in time and used for comparison over time to look for changes. The baseline can be a measurement taken before treatment and then used to observe whether the treatment is effective. For example, the size of a tumor can be measured before (baseline) and after treatment to observe whether the treatment is effective.

[0145] The term "about" or "approximately" refers to an acceptable error for a particular value as determined by someone skilled in the art, depending in part on how the value is measured or determined. In some embodiments, the term "about" or "approximately" means within 1, 2, 3, or 4 standard deviations. In some embodiments, the term "about" or "approximately" means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

[0146] The term "untreated patient" refers to a patient with a specific condition or disease (such as desmoidoma or multiple myeloma) who has not previously received treatment for that condition or disease. In one embodiment, the untreated patient has not previously undergone surgery. In another embodiment, the untreated patient has not been treated with any medication. In one exemplary embodiment, the untreated patient has not been treated with a tyrosine kinase inhibitor (such as sorafenib).

[0147] Unless the context otherwise requires, the terms “comprise”, “comprises”, and “comprising” are used based on the clear understanding that they should be interpreted as inclusive rather than exclusive, and that the applicant intends each of these words to be interpreted in the interpretation of this patent (including the appended claims).

[0148] II. Composition

[0149] This disclosure relates to compounds comprising formula (I).

[0150]

[0151] Or a pharmaceutically acceptable salt composition thereof, wherein the composition provides a mean maximum plasma concentration of the drug greater than 100 ng / ml (C max In some respects, compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof provide a mean maximum plasma concentration (C0.05) of about 150 ng / ml to about 500 ng / ml. max In some respects, compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof provide a mean maximum plasma concentration (C0) of about 200 ng / ml to about 450 ng / ml. max In some respects, compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof provide a mean maximum plasma concentration (C0.05) of about 250 ng / ml to about 400 ng / ml. max In some aspects, compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof provide mean maximum plasma drug concentrations (C0) of about 125 ng / ml, about 150 ng / ml, about 175 ng / ml, about 200 ng / ml, about 225 ng / ml, about 250 ng / ml, about 275 ng / ml, about 300 ng / ml, about 325 ng / ml, about 350 ng / ml, about 375 ng / ml, about 400 ng / ml, about 425 ng / ml, about 450 ng / ml, about 475 ng / ml, or about 500 ng / ml. max ).

[0152] In some respects, the pharmaceutically acceptable salt of the compound of formula (I) is hydrobromide. In other respects, the pharmaceutically acceptable salt of the compound of formula (I) is dihydrobromide.

[0153] In some respects, the composition comprises a compound of formula (I) in the form of dihydrobromide and provides a mean maximum plasma drug concentration (C0.05) greater than 100 ng / ml. max In some aspects, the composition comprises a compound of formula (I) in the form of dihydrobromide and provides a mean maximum plasma concentration (C0.05) of about 150 ng / ml to about 500 ng / ml. max In some aspects, the composition comprises a compound of formula (I) in the form of dihydrobromide and provides a mean maximum plasma concentration (C0) of about 200 ng / ml to about 450 ng / ml. max In some aspects, the composition comprises a compound of formula (I) in the form of dihydrobromide and provides a mean maximum plasma concentration (C0) of about 250 ng / ml to about 400 ng / ml. max In some aspects, the composition comprises a compound of formula (I) in the form of dihydrobromide and provides a mean maximum plasma concentration (C1) of about 125 ng / ml, about 150 ng / ml, about 175 ng / ml, about 200 ng / ml, about 225 ng / ml, about 250 ng / ml, about 275 ng / ml, about 300 ng / ml, about 325 ng / ml, about 350 ng / ml, about 375 ng / ml, about 400 ng / ml, about 425 ng / ml, about 450 ng / ml, about 475 ng / ml, or about 500 ng / ml. max ).

[0154] Compositions containing a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) may be administered to a subject via oral, parenteral (e.g., subcutaneous, intravenous, intramuscular, intrasternal, and infusion techniques), rectal, intranasal, topical, or percutaneous (e.g., by using a patch) route. In some aspects, compositions containing a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) may be administered to a subject orally.

[0155] In some aspects, compositions containing a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) are in solid form. In one aspect, compositions containing a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) are in tablet or capsule form.

[0156] In some respects, compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) may additionally comprise one or more pharmaceutically acceptable excipients. For example, for oral administration, microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate, and glycine may be used with various disintegrants such as starch (preferably corn, potato, or cassava starch), methylcellulose, alginate, and certain complex silicates, together with granulation binders such as polyvinylpyrrolidone, sucrose, gelatin, and gum arabic, in tablets. Additionally, lubricants such as magnesium stearate, sodium dodecyl sulfate, and talc are commonly used for tableting purposes. Similar types of solid compositions may also be used as fillers in gelatin capsules. In this regard, preferred materials include lactose or milk sugar and high molecular weight polyethylene glycol. When an aqueous suspension and / or elixir is required for oral administration, the active ingredient may be combined with various sweeteners or flavorings, colorants or dyes, and, if necessary, with emulsifiers and / or suspending agents, as well as diluents such as water, ethanol, propylene glycol, glycerin, and various similar combinations thereof.

[0157] In some aspects, compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) may be administered to patients in need for the treatment of desmoidoma or multiple myeloma. The composition may comprise an amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) in the range of, for example, 25 mg to 350 mg, 50 mg to 325 mg, 75 mg to 300 mg, 100 mg to 275 mg, 125 mg to 250 mg, 150 mg to 225 mg, or 175 mg to 200 mg. In some aspects, compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) may be administered in the range of, for example, 50 mg to 300 mg, 100 mg to 250 mg, and 150 mg to 200 mg. The composition may contain, for example, an amount of formula (I) compound or a pharmaceutically acceptable salt thereof (e.g., in dihydrobromide form) of about 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, and 350 mg. In some aspects, the composition may contain, for example, an amount of formula (I) compound or a pharmaceutically acceptable salt thereof (e.g., in dihydrobromide form) of about 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, and 350 mg. In some aspects, the composition may be administered once daily. In other aspects, the composition may be administered twice daily. For example, the composition may contain 50 mg of nirogasstat or a pharmaceutically acceptable salt thereof and be administered once daily. In other examples, the composition may contain 50 mg of nirogasstat or a pharmaceutically acceptable salt thereof and be administered twice daily. The composition may contain 100 mg nirogasstat or a pharmaceutically acceptable salt thereof, and be administered once daily. In other examples, the composition may contain 100 mg nirogasstat or a pharmaceutically acceptable salt thereof, and be administered twice daily. In other examples, the composition may contain 150 mg nirogasstat or a pharmaceutically acceptable salt thereof, and be administered once daily. In other examples, the composition may contain 150 mg nirogasstat or a pharmaceutically acceptable salt thereof, and be administered twice daily.

[0158] One embodiment is a solid oral pharmaceutical composition (such as tablets or capsules) containing 50 mg (free base equivalent dose) of nirogalstat or a pharmaceutically acceptable salt thereof (such as nirogalstat dihydrobromide), which provides less than 200 ng / mL (such as less than 190 ng / mL) of C10 when initially administered orally to a human subject. max In one embodiment, the solid pharmaceutical composition provides about 100 to about 200 ng / mL of C upon initial oral administration to a human subject. max .

[0159] Another embodiment is a solid oral pharmaceutical composition (such as tablets or capsules) containing 50 mg (free base equivalent dose) of nirogalstat or a pharmaceutically acceptable salt thereof (such as nirogalstat dihydrobromide), which provides an AUC of less than 725 ng·h / mL upon initial oral administration to a human subject. last In one embodiment, the solid oral pharmaceutical composition exhibits a C10 concentration of less than 200 ng / mL (such as less than 190 ng / mL, or about 100 to about 200 ng / mL) when initially administered orally to a human subject. max .

[0160] Another embodiment is a solid oral pharmaceutical composition (such as tablets or capsules) containing 50 mg (free base equivalent dose) of nirogalstat or a pharmaceutically acceptable salt thereof (such as nirogalstat dihydrobromide), which provides an AUC of about 375 to about 725 ng·h / mL when initially administered orally to a human subject. last In one embodiment, the solid oral pharmaceutical composition exhibits a C10 concentration of less than 200 ng / mL (such as less than 190 ng / mL, or about 100 to about 200 ng / mL) when initially administered orally to a human subject. max .

[0161] Another embodiment is a solid oral pharmaceutical composition (such as tablets or capsules) containing 50 mg (free base equivalent dose) of nirogalstat or a pharmaceutically acceptable salt thereof (such as nirogalstat dihydrobromide), which provides an AUC of less than 725 ng·h / mL when initially administered orally to a human subject. inf In one embodiment, the solid oral pharmaceutical composition exhibits a C10 concentration of less than 200 ng / mL (such as less than 190 ng / mL, or about 100 to about 200 ng / mL) when initially administered orally to a human subject. max .

[0162] Another embodiment is a solid oral pharmaceutical composition (such as tablets or capsules) containing 50 mg (free base equivalent dose) of nirogalstat or a pharmaceutically acceptable salt thereof (such as nirogalstat dihydrobromide), which provides an AUC of about 375 to about 725 ng·h / mL when initially administered orally to a human subject. inf In one embodiment, the solid oral pharmaceutical composition exhibits a C10 concentration of less than 200 ng / mL (such as less than 190 ng / mL, or about 100 to about 200 ng / mL) when initially administered orally to a human subject. max .

[0163] One embodiment is a solid oral pharmaceutical composition (such as tablets or capsules) containing 100 mg (free base equivalent dose) of nirogalstat or a pharmaceutically acceptable salt thereof (such as nirogalstat dihydrobromide), which provides less than 600 ng / mL (such as less than 570 ng / mL, or about 300 to about 570 ng / mL) of C10 when initially administered orally to a human subject. max .

[0164] Another embodiment is a solid oral pharmaceutical composition (such as tablets or capsules) containing 100 mg (free base equivalent dose) of nirogalstat or a pharmaceutically acceptable salt thereof (such as nirogalstat dihydrobromide), which provides an AUC of less than 2300 ng·h / mL upon initial oral administration to a human subject. last In one embodiment, the solid oral pharmaceutical composition exhibits a C10 concentration of less than 600 ng / mL (such as less than 570 ng / mL, or about 300 to about 570 ng / mL) when initially administered orally to a human subject. max .

[0165] Another embodiment is a solid oral pharmaceutical composition (such as tablets or capsules) containing 100 mg (free base equivalent) of nirogalstat or a pharmaceutically acceptable salt thereof (such as nirogalstat dihydrobromide), which provides an AUC of about 1200 to about 2300 ng·h / mL in an initial oral administration to a human subject. last In one embodiment, the solid oral pharmaceutical composition exhibits a C10 concentration of less than 600 ng / mL (such as less than 570 ng / mL, or about 300 to about 570 ng / mL) when initially administered orally to a human subject. max .

[0166] Another embodiment is a solid oral pharmaceutical composition (such as tablets or capsules) containing 100 mg (free base equivalent dose) of nirogalstat or a pharmaceutically acceptable salt thereof (such as nirogalstat dihydrobromide), which provides an AUC of less than 2300 ng·h / mL upon initial oral administration to a human subject. inf In one embodiment, the solid oral pharmaceutical composition exhibits a C10 concentration of less than 600 ng / mL (such as less than 570 ng / mL, or about 300 to about 570 ng / mL) when initially administered orally to a human subject. max .

[0167] Another embodiment is a solid oral pharmaceutical composition (such as tablets or capsules) containing 100 mg (free base equivalent) of nirogalstat or a pharmaceutically acceptable salt thereof (such as nirogalstat dihydrobromide), which provides an AUC of about 1200 to about 2300 ng·h / mL in an initial oral administration to a human subject. inf In one embodiment, the solid oral pharmaceutical composition exhibits a C10 concentration of less than 600 ng / mL (such as less than 570 ng / mL, or about 300 to about 570 ng / mL) when initially administered orally to a human subject. max .

[0168] One embodiment is a solid oral pharmaceutical composition (such as tablets or capsules) containing 150 mg (free base equivalent dose) of nirogalstat or a pharmaceutically acceptable salt thereof (such as nirogalstat dihydrobromide), which provides less than 1000 ng / mL (such as less than 950 ng / mL, or about 480 to about 950 ng / mL) of C when initially administered orally to a human subject. max .

[0169] Another embodiment is a solid oral pharmaceutical composition (such as tablets or capsules) containing 150 mg (free base equivalent dose) of nirogalstat or a pharmaceutically acceptable salt thereof (such as nirogalstat dihydrobromide), which provides an AUC of less than 4000 ng·h / mL upon initial oral administration to a human subject. last In one embodiment, the solid oral pharmaceutical composition exhibits a C10 concentration of less than 1000 ng / mL (such as less than 950 ng / mL, or about 480 to about 950 ng / mL) when initially administered orally to a human subject. max .

[0170] Another embodiment is a solid oral pharmaceutical composition (such as tablets or capsules) containing 150 mg (free base equivalent) of nirogalstat or a pharmaceutically acceptable salt thereof (such as nirogalstat dihydrobromide), which provides an AUC of about 2000 to about 4000 ng·h / mL in an initial oral administration to a human subject. last In one embodiment, the solid oral pharmaceutical composition exhibits a C10 concentration of less than 1000 ng / mL (such as less than 950 ng / mL, or about 480 to about 950 ng / mL) when initially administered orally to a human subject. max .

[0171] Another embodiment is a solid oral pharmaceutical composition (such as tablets or capsules) containing 150 mg (free base equivalent dose) of nirogalstat or a pharmaceutically acceptable salt thereof (such as nirogalstat dihydrobromide), which provides an AUC of less than 4000 ng·h / mL upon initial oral administration to a human subject. inf In one embodiment, the solid oral pharmaceutical composition exhibits a C10 concentration of less than 1000 ng / mL (such as less than 950 ng / mL, or about 480 to about 950 ng / mL) when initially administered orally to a human subject. max .

[0172] Another embodiment is a solid oral pharmaceutical composition (such as tablets or capsules) containing 150 mg (free base equivalent) of nirogalstat or a pharmaceutically acceptable salt thereof (such as nirogalstat dihydrobromide), which provides an AUC of about 2000 to about 4000 ng·h / mL in an initial oral administration to a human subject. inf In one embodiment, the solid oral pharmaceutical composition exhibits a C10 concentration of less than 1000 ng / mL (such as less than 950 ng / mL, or about 480 to about 950 ng / mL) when initially administered orally to a human subject. max .

[0173] III. Treatment

[0174] A. Desmoidoma

[0175] Nilogasstat can be administered to patients to treat desmoidoma. In some aspects, methods of treating desmoidoma in patients in need include administering an oral dose of nilogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides a mean maximum plasma concentration of the drug greater than 100 ng / ml (C0.05). max In some respects, methods for treating desmoidomas in patients of need include administering to the patient an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides a mean maximum plasma concentration (C0.05) of the drug from about 150 ng / ml to about 500 ng / ml. max In some respects, methods for treating desmoidomas in patients of need include administering to the patient an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides a mean maximum plasma concentration (C0.05) of the drug from about 200 ng / ml to about 500 ng / ml. maxIn some respects, methods for treating desmoidomas in patients of need include administering to the patient an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides a mean maximum plasma concentration (C0.05) of the drug from about 250 ng / ml to about 500 ng / ml. max In some respects, methods of treating desmoidomas in patients of need include administering to the patient an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides a mean maximum plasma concentration (C0) of about 125 ng / ml, about 150 ng / ml, about 175 ng / ml, about 200 ng / ml, about 225 ng / ml, about 250 ng / ml, about 275 ng / ml, about 300 ng / ml, about 325 ng / ml, about 350 ng / ml, about 375 ng / ml, about 400 ng / ml, about 425 ng / ml, about 450 ng / ml, about 475 ng / ml, or about 500 ng / ml. max ).

[0176] In some respects, methods for treating desmoidomas in patients of need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of less than 700 ng·h / ml. inf In some respects, methods for treating desmoidomas in patients of need include administering to the patient an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 200 ng·h / ml to about 650 ng·h / ml. inf In some respects, methods for treating desmoidomas in patients of need include administering to the patient an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 250 ng·h / ml to about 650 ng·h / ml. inf In some respects, methods for treating desmoidomas in patients of need include administering to the patient an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 300 ng·h / ml to about 650 ng·h / ml. inf). In some respects, methods for treating desmoidomas in patients of need include administering to the patient an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 200 ng·h / ml, about 225 ng·h / ml, about 250 ng·h / ml, about 275 ng·h / ml, about 300 ng·h / ml, about 325 ng·h / ml, about 350 ng·h / ml, about 375 ng·h / ml, about 400 ng·h / ml, about 425 ng·h / ml, about 450 ng·h / ml, about 475 ng·h / ml, about 500 ng·h / ml, about 525 ng·h / ml, about 550 ng·h / ml, about 575 ng·h / ml, about 600 ng·h / ml, about 625 ng·h / ml, or about 675 ng·h / ml. inf ).

[0177] In some respects, methods for treating desmoidoma include administering an oral dosage form containing 50 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to patients in need.

[0178] In some respects, methods for treating desmoidoma in patients of need include administering to the patient an oral dose of 50 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides a mean maximum plasma concentration of the drug greater than 100 ng / ml (C0.05). max In some respects, methods for treating desmoidomas in patients of need include administering to the patient an oral dose of 50 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides a mean maximum plasma concentration (C0.05) of the drug from about 150 ng / ml to about 500 ng / ml. max In some respects, methods for treating desmoidomas in patients of need include administering to the patient an oral dose of 50 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides a mean maximum plasma concentration (C0.05) of the drug from about 200 ng / ml to about 500 ng / ml. max In some respects, methods for treating desmoidomas in patients of need include administering to the patient an oral dose of 50 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides a mean maximum plasma concentration (C0.05) of the drug from about 250 ng / ml to about 500 ng / ml. maxIn some respects, methods of treating desmoidoma in patients of need include administering to the patient an oral dose of 50 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides a mean maximum plasma concentration (C0) of about 125 ng / ml, about 150 ng / ml, about 175 ng / ml, about 200 ng / ml, about 225 ng / ml, about 250 ng / ml, about 275 ng / ml, about 300 ng / ml, about 325 ng / ml, about 350 ng / ml, about 375 ng / ml, about 400 ng / ml, about 425 ng / ml, about 450 ng / ml, about 475 ng / ml, or about 500 ng / ml. max ).

[0179] In some respects, methods for treating desmoidomas in patients of need include administering to the patient an oral dose of 50 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of less than 700 ng·h / ml. inf In some respects, methods for treating desmoidomas in patients of need include administering to the patient an oral dose of 50 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 200 ng·h / ml to about 650 ng·h / ml. inf In some respects, methods for treating desmoidomas in patients of need include administering to the patient an oral dose of 50 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 250 ng·h / ml to about 650 ng·h / ml. inf In some respects, methods for treating desmoidomas in patients of need include administering to the patient an oral dose of 50 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 300 ng·h / ml to about 650 ng·h / ml. infIn some respects, methods of treating desmoidomas in patients in need include administering to the patient an oral dose of 50 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides approximately 200 ng·h / ml, approximately 225 ng·h / ml, approximately 250 ng·h / ml, approximately 275 ng·h / ml, approximately 300 ng·h / ml, approximately 325 ng·h / ml, approximately 350 ng·h / ml, approximately 375 ng·h / ml, approximately 400 ng·h / ml, approximately 425 ng·h / ml, approximately 450 ng·h / ml, approximately 475 ng·h / ml, approximately 500 ng·h / ml, approximately 525 ng·h / ml, approximately 550 ng·h / ml, approximately 575 g. The area under the plasma curve (AUC) at h / ml, approximately 600 ng·h / ml, approximately 625 ng·h / ml, or approximately 675 ng·h / ml. inf ).

[0180] In some respects, methods for treating desmoidoma in patients in need include administering 300 mg / day of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide).

[0181] In some aspects, methods of treating desmoidoma include oral administration of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide). In some aspects, methods of treating desmoidoma include oral administration of nirogasstat or a pharmaceutically acceptable salt thereof in a solid dosage form (e.g., in the form of dihydrobromide). In some aspects, the solid dosage form is a tablet or capsule.

[0182] In some aspects, methods of treating desmoidoma include administering nirogalostat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) once daily. In other aspects, methods of treating desmoidoma include administering nirogalostat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) two, three, or four times daily. If nirogalostat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) is administered more than once daily, the total daily dose for each administration may be the same or different. For example, if 300 mg of nirogalostatat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) is administered twice daily, the patient may receive two 150 mg doses (e.g., a 150 mg dose at 8 a.m. and a 150 mg dose at 8 p.m.) or a 100 mg dose in the morning and a 200 mg dose in the evening. Each dose may also consist of more than one solid dosage form. For example, a single 150 mg dose (i.e., the morning dose as part of a total daily dose of 300 mg administered in two separate doses) may be administered as three 50 mg tablets.

[0183] In one embodiment, a patient with desmoidoma is treated with 150 mg of nirogalstat twice daily (total daily dose of 300 mg nirogalstat). In a preferred embodiment, nirogalstat is administered in the form of its dihydrobromide salt. In a preferred embodiment, the dosage is varied due to adverse reactions as follows:

[0184] In one implementation, the dosage is modified for selected serious adverse reactions as described in Table 1 below. All adverse reactions or events are graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, which is incorporated herein by reference. For adverse events (or adverse reactions) not listed in the CTCAE or serious adverse events, the following grading system is used: Grade 1 indicates mild; asymptomatic or mild symptoms; clinical or diagnostic observation only; not suitable for treatment. Grade 3 indicates serious or medically significant but not immediately life-threatening; requires hospitalization or prolonged hospitalization; contraindicated; restricts activities of daily living. Activities of daily living include bathing, dressing and undressing, eating, toileting, taking medications, and not being bedridden.

[0185] Table 1: Dosage Modifications for Adverse Reactions

[0186]

[0187]

[0188] ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; ULN = Upper limit of normal

[0189] In an alternative implementation, for serious adverse reactions other than those listed in Table 1, or in the event of life-threatening adverse reactions, nirogalstat should be discontinued until the reaction resolves to grade ≤1 or baseline. Treatment with nirogalstat may be restarted at a dose of 100 mg twice daily, taking into account the potential benefits and the likelihood of recurrence of adverse reactions. Nirogalstat is permanently discontinued upon re-challenge at a reduced dose (i.e., 100 mg twice daily) in the event of a recurrence of serious or life-threatening adverse reactions.

[0190] B. Multiple myeloma

[0191] Nilogasstat can also be used to treat patients with multiple myeloma.

[0192] In some respects, methods for treating multiple myeloma in patients in need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides a mean maximum plasma concentration of the drug greater than 100 ng / ml (C0.05). maxIn some respects, methods for treating multiple myeloma in patients in need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides a mean maximum plasma concentration (C0.05) of the drug from about 150 ng / ml to about 500 ng / ml. max In some respects, methods for treating multiple myeloma in patients in need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides a mean maximum plasma concentration (C0.05) of the drug from about 200 ng / ml to about 500 ng / ml. max In some respects, methods for treating multiple myeloma in patients in need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides a mean maximum plasma concentration (C0.05) of the drug from about 250 ng / ml to about 500 ng / ml. max In some respects, methods of treating multiple myeloma in patients of need include administering to the patient an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides a mean maximum plasma concentration (C0) of about 125 ng / ml, about 150 ng / ml, about 175 ng / ml, about 200 ng / ml, about 225 ng / ml, about 250 ng / ml, about 275 ng / ml, about 300 ng / ml, about 325 ng / ml, about 350 ng / ml, about 375 ng / ml, about 400 ng / ml, about 425 ng / ml, about 450 ng / ml, about 475 ng / ml, or about 500 ng / ml. max ).

[0193] In some respects, methods for treating multiple myeloma in patients in need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides a mean maximum plasma concentration of the drug greater than 225 ng / ml (C0.05). max In some respects, methods for treating multiple myeloma in patients in need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides a mean maximum plasma concentration (C0.05) of the drug from about 250 ng / ml to about 750 ng / ml. maxIn some respects, methods for treating multiple myeloma in patients in need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides a mean maximum plasma concentration (C0.05) of the drug from about 300 ng / ml to about 750 ng / ml. max In some respects, methods for treating multiple myeloma in patients in need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides a mean maximum plasma concentration (C0.05) of the drug from about 350 ng / ml to about 750 ng / ml. max In some aspects, methods of treating multiple myeloma in patients of need include administering to the patient an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides a mean maximum plasma concentration (C0) of about 250 ng / ml, about 275 ng / ml, about 300 ng / ml, about 325 ng / ml, about 350 ng / ml, about 375 ng / ml, about 400 ng / ml, about 425 ng / ml, about 450 ng / ml, about 475 ng / ml, about 500 ng / ml, about 525 ng / ml, about 550 ng / ml, about 575 ng / ml, about 600 ng / ml, about 625 ng / ml, about 650 ng / ml, about 675 ng / ml, about 700 ng / ml, about 725 ng / ml, or about 750 ng / ml. max ).

[0194] In some respects, methods for treating multiple myeloma in patients in need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of less than 700 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients of need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 200 ng·h / ml to about 650 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients in need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 250 ng·h / ml to about 650 ng·h / ml. infIn some respects, methods for treating multiple myeloma in patients of need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 300 ng·h / ml to about 650 ng·h / ml. inf ). In some respects, methods of treating multiple myeloma in patients of need include administering to the patient an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 200 ng·h / ml, about 225 ng·h / ml, about 250 ng·h / ml, about 275 ng·h / ml, about 300 ng·h / ml, about 325 ng·h / ml, about 350 ng·h / ml, about 375 ng·h / ml, about 400 ng·h / ml, about 425 ng·h / ml, about 450 ng·h / ml, about 475 ng·h / ml, about 500 ng·h / ml, about 525 ng·h / ml, about 550 ng·h / ml, about 575 ng·h / ml, about 600 ng·h / ml, about 625 ng·h / ml, or about 675 ng·h / ml. inf ).

[0195] In some respects, methods for treating multiple myeloma in patients in need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of less than 3000 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients in need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 200 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients in need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 250 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients in need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 300 ng·h / ml to about 2950 ng·h / ml. infIn some respects, methods for treating multiple myeloma in patients in need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 350 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients of need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 400 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients in need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 450 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients of need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 500 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients of need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 550 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients in need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 600 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients in need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 650 ng·h / ml to about 2950 ng·h / ml. infIn some respects, methods for treating multiple myeloma in patients in need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 700 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients in need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 750 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients in need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 800 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients in need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 850 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients in need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 900 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients in need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 950 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients of need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 1000 ng·h / ml to about 2950 ng·h / ml. in fIn some respects, methods for treating multiple myeloma in patients in need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 1050 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients in need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 1100 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients in need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 1150 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients in need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 1200 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients in need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 1250 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients of need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 1350 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients in need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 1400 ng·h / ml to about 2950 ng·h / ml. infIn some respects, methods for treating multiple myeloma in patients in need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 1450 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients in need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 1500 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients of need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 1550 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients in need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 1600 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients in need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 1650 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients in need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 1700 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients of need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 1750 ng·h / ml to about 2950 ng·h / ml. infIn some respects, methods for treating multiple myeloma in patients in need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 1800 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients in need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 1850 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients in need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 1900 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients in need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 1950 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients in need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 2000 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients in need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 2050 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients in need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 2100 ng·h / ml to about 2950 ng·h / ml. infIn some respects, methods for treating multiple myeloma in patients in need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 2150 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients in need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 2200 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients in need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 2250 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients in need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 2300 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients in need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 2350 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients of need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 2400 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients in need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 2450 ng·h / ml to about 2950 ng·h / ml. infIn some respects, methods for treating multiple myeloma in patients of need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 2500 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients in need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 2550 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients in need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 2600 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients in need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 2650 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients in need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 2700 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients in need include administering an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 2750 ng·h / ml to about 2950 ng·h / ml. infIn some respects, methods of treating multiple myeloma in patients in need include administering to the patient an oral dose of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides approximately 200 ng·h / ml, approximately 225 ng·h / ml, approximately 250 ng·h / ml, approximately 275 ng·h / ml, approximately 300 ng·h / ml, approximately 325 ng·h / ml, approximately 350 ng·h / ml, approximately 375 ng·h / ml, approximately 400 ng·h / ml, approximately 425 ng·h / ml, approximately 450 ng·h / ml, approximately 475 ng·h / ml, approximately 500 ng·h / ml, approximately 525 ng·h / ml, approximately 550 ng·h / ml, or approximately 575 g. h / ml, approximately 600 ng·h / ml, approximately 625 ng·h / ml, approximately 675 ng·h / ml, approximately 700 ng·h / ml, approximately 725 ng·h / ml, approximately 750 ng·h / ml, approximately 775 ng·h / ml, approximately 800 ng·h / ml, approximately 825 ng·h / ml, approximately 850 ng·h / ml, approximately 875 ng·h / ml, approximately 900 ng·h / ml, approximately 925 ng·h / ml, approximately 950 ng·h / ml Approximately 975 ng·h / ml, approximately 1000 ng·h / ml, approximately 1025 ng·h / ml, approximately 1050 ng·h / ml, approximately 1075 ng·h / ml, approximately 1100 ng·h / ml, approximately 1125 ng·h / ml, approximately 1150 ng·h / ml, approximately 1175 ng·h / ml, approximately 1200 ng·h / ml, approximately 1225 ng·h / ml, approximately 1250 ng·h / ml, approximately 1275 ng·h / ml, approximately 1300 ng·h / ml g·h / ml, approximately 1325 ng·h / ml, approximately 1350 ng·h / ml, approximately 1375 ng·h / ml, approximately 1400 ng·h / ml, approximately 1425 ng·h / ml, approximately 1450 ng·h / ml, approximately 1475 ng·h / ml, approximately 1500 ng·h / ml, approximately 1525 ng·h / ml, approximately 1550 ng·h / ml, approximately 1575 ng·h / ml, approximately 1600 ng·h / ml, approximately 1625 ng·h / ml, approximately 1650 ng·h / ml, approximately 1675 ng·h / mlg·h / ml, approximately 1700 ng·h / ml, approximately 1725 ng·h / ml, approximately 1750 ng·h / ml, approximately 1775 ng·h / ml, approximately 1800 ng·h / ml, approximately 1825 ng·h / ml, approximately 1850 ng·h / ml, approximately 1875 ng·h / ml, approximately 1900 ng·h / ml, approximately 1925 ng·h / ml, approximately 1950 ng·h / ml, approximately 2000 ng·h / ml, approximately 2025 ng·h / ml, approximately 2050 ng·h / ml, approximately 2100 ng·h / ml g·h / ml, approximately 2125 ng·h / ml, approximately 2150 ng·h / ml, approximately 2175 ng·h / ml, approximately 2200 ng·h / ml, approximately 2225 ng·h / ml, approximately 2250 ng·h / ml, approximately 2275 ng·h / ml, approximately 2300 ng·h / ml, approximately 2325 ng·h / ml, approximately 2550 ng·h / ml, approximately 2575 ng·h / ml, approximately 2600 ng·h / ml, approximately 2625 ng·h / ml, approximately 2650 ng·h / ml, approximately 2675 ng·h / ml The area under the plasma curve (AUC) at g·h / ml, approximately 2700 ng·h / ml, approximately 2725 ng·h / ml, approximately 2750 ng·h / ml, approximately 2775 ng·h / ml, approximately 2800 ng·h / ml, approximately 2825 ng·h / ml, approximately 2850 ng·h / ml, approximately 2875 ng·h / ml, approximately 2900 ng·h / ml, approximately 2925 ng·h / ml, or approximately 2950 ng·h / ml. inf ).

[0196] In some aspects, methods for treating multiple myeloma include administering 200 mg / day of nirogalstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to a patient in need. For example, the method may include administering 100 mg / day of nirogalstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) twice daily. In some aspects, methods for treating multiple myeloma include administering 100 mg / day of nirogalstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to a patient in need. In some aspects, methods for treating multiple myeloma include administering 100 mg / day of nirogalstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to a patient in need. In some aspects, methods for treating multiple myeloma include administering 50 mg / day of nirogalstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to a patient in need.

[0197] In some respects, methods for treating multiple myeloma in patients in need include administering to the patient an oral dose of 50 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides a mean maximum plasma concentration of the drug greater than 100 ng / ml (C0.05). max In some respects, methods of treating multiple myeloma in patients in need include administering to the patient an oral dose of 50 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides a mean maximum plasma concentration (C0.05) of the drug from about 150 ng / ml to about 500 ng / ml. max In some respects, methods of treating multiple myeloma in patients in need include administering to the patient an oral dose of 50 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides a mean maximum plasma concentration (C0.05) of the drug from about 200 ng / ml to about 500 ng / ml. max In some respects, methods of treating multiple myeloma in patients in need include administering to the patient an oral dose of 50 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides a mean maximum plasma concentration (C0.05) of the drug from about 250 ng / ml to about 500 ng / ml. max In some respects, methods of treating multiple myeloma in patients of need include administering to the patient an oral dose of 50 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides a mean maximum plasma concentration (C0) of about 125 ng / ml, about 150 ng / ml, about 175 ng / ml, about 200 ng / ml, about 225 ng / ml, about 250 ng / ml, about 275 ng / ml, about 300 ng / ml, about 325 ng / ml, about 350 ng / ml, about 375 ng / ml, about 400 ng / ml, about 425 ng / ml, about 450 ng / ml, about 475 ng / ml, or about 500 ng / ml. max ).

[0198] In some respects, methods of treating multiple myeloma in patients in need include administering to the patient an oral dose of 100 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides a mean maximum plasma concentration of the drug greater than 225 ng / ml (C0.05). maxIn some respects, methods of treating multiple myeloma in patients in need include administering to the patient an oral dose of 100 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides a mean maximum plasma concentration (C0.05) of the drug from about 250 ng / ml to about 750 ng / ml. max In some respects, methods of treating multiple myeloma in patients in need include administering to the patient an oral dose of 100 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides a mean maximum plasma concentration (C0.05) of the drug from about 300 ng / ml to about 750 ng / ml. max In some respects, methods of treating multiple myeloma in patients in need include administering to the patient an oral dose of 100 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides a mean maximum plasma concentration (C0.05) of the drug from about 350 ng / ml to about 750 ng / ml. max In some respects, methods of treating multiple myeloma in patients of need include administering to the patient an oral dose of 100 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides a mean maximum plasma concentration (C0.05) of about 250 ng / ml, about 275 ng / ml, about 300 ng / ml, about 325 ng / ml, about 350 ng / ml, about 375 ng / ml, about 400 ng / ml, about 425 ng / ml, about 450 ng / ml, about 475 ng / ml, about 500 ng / ml, about 525 ng / ml, about 550 ng / ml, about 575 ng / ml, about 600 ng / ml, about 625 ng / ml, about 650 ng / ml, about 675 ng / ml, about 700 ng / ml, about 725 ng / ml, or about 750 ng / ml. max ).

[0199] In some respects, methods for treating multiple myeloma in patients in need include administering to the patient an oral dose of 50 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of less than 700 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients in need include administering to the patient an oral dose of 50 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 200 ng·h / ml to about 650 ng·h / ml. infIn some respects, methods for treating multiple myeloma in patients in need include administering to the patient an oral dose of 50 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 250 ng·h / ml to about 650 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients in need include administering to the patient an oral dose of 50 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 300 ng·h / ml to about 650 ng·h / ml. inf In some respects, methods of treating multiple myeloma in patients in need include administering to the patient an oral dose of 50 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides approximately 200 ng·h / ml, approximately 225 ng·h / ml, approximately 250 ng·h / ml, approximately 275 ng·h / ml, approximately 300 ng·h / ml, approximately 325 ng·h / ml, approximately 350 ng·h / ml, approximately 375 ng·h / ml, approximately 400 ng·h / ml, approximately 425 ng·h / ml, approximately 450 ng·h / ml, approximately 475 ng·h / ml, approximately 500 ng·h / ml, approximately 525 ng·h / ml, approximately 550 ng·h / ml, approximately 575 g. The area under the plasma curve (AUC) at h / ml, approximately 600 ng·h / ml, approximately 625 ng·h / ml, or approximately 675 ng·h / ml. inf ).

[0200] In some respects, methods for treating multiple myeloma in patients in need include administering an oral dose of 100 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) to the patient, wherein the oral dose provides an in vivo plasma area under the curve (AUC) of less than 3000 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients in need include administering to the patient an oral dose of 100 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 200 ng·h / ml to about 2950 ng·h / ml. infIn some respects, methods for treating multiple myeloma in patients of need include administering to the patient an oral dose of 100 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 250 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients in need include administering to the patient an oral dose of 100 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 300 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients in need include administering to the patient an oral dose of 100 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 350 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients in need include administering to the patient an oral dose of 100 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 400 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients in need include administering to the patient an oral dose of 100 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 450 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients of need include administering to the patient an oral dose of 100 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 500 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients of need include administering to the patient an oral dose of 100 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 550 ng·h / ml to about 2950 ng·h / ml. infIn some respects, methods for treating multiple myeloma in patients of need include administering to the patient an oral dose of 100 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 600 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients of need include administering to the patient an oral dose of 100 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 650 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients in need include administering to the patient an oral dose of 100 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 700 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients in need include administering to the patient an oral dose of 100 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 750 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients of need include administering to the patient an oral dose of 100 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 800 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients in need include administering to the patient an oral dose of 100 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 850 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients in need include administering to the patient an oral dose of 100 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 900 ng·h / ml to about 2950 ng·h / ml. infIn some respects, methods for treating multiple myeloma in patients in need include administering to the patient an oral dose of 100 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 950 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients of need include administering to the patient an oral dose of 100 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 1000 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients in need include administering to the patient an oral dose of 100 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 1050 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients in need include administering to the patient an oral dose of 100 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 1100 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients of need include administering to the patient an oral dose of 100 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 1150 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients in need include administering to the patient an oral dose of 100 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 1200 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients of need include administering to the patient an oral dose of 100 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 1250 ng·h / ml to about 2950 ng·h / ml. infIn some respects, methods for treating multiple myeloma in patients of need include administering to the patient an oral dose of 100 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 1350 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients in need include administering to the patient an oral dose of 100 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 1400 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients of need include administering to the patient an oral dose of 100 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 1450 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients of need include administering to the patient an oral dose of 100 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 1500 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients of need include administering to the patient an oral dose of 100 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 1550 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients of need include administering to the patient an oral dose of 100 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 1600 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients of need include administering to the patient an oral dose of 100 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 1650 ng·h / ml to about 2950 ng·h / ml. infIn some respects, methods for treating multiple myeloma in patients in need include administering to the patient an oral dose of 100 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 1700 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients of need include administering to the patient an oral dose of 100 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 1750 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients of need include administering to the patient an oral dose of 100 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 1800 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients in need include administering to the patient an oral dose of 100 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 1850 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients in need include administering to the patient an oral dose of 100 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 1900 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients in need include administering to the patient an oral dose of 100 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 1950 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients of need include administering to the patient an oral dose of 100 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 2000 ng·h / ml to about 2950 ng·h / ml. infIn some respects, methods for treating multiple myeloma in patients in need include administering to the patient an oral dose of 100 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 2050 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients of need include administering to the patient an oral dose of 100 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 2100 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients of need include administering to the patient an oral dose of 100 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 2150 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients of need include administering to the patient an oral dose of 100 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 2200 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients of need include administering to the patient an oral dose of 100 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 2250 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients of need include administering to the patient an oral dose of 100 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 2300 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients of need include administering to the patient an oral dose of 100 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 2350 ng·h / ml to about 2950 ng·h / ml. infIn some respects, methods for treating multiple myeloma in patients in need include administering to the patient an oral dose of 100 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 2400 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients in need include administering to the patient an oral dose of 100 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 2450 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients of need include administering to the patient an oral dose of 100 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 2500 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients of need include administering to the patient an oral dose of 100 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 2550 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients in need include administering to the patient an oral dose of 100 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 2600 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients in need include administering to the patient an oral dose of 100 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 2650 ng·h / ml to about 2950 ng·h / ml. inf In some respects, methods for treating multiple myeloma in patients of need include administering to the patient an oral dose of 100 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 2700 ng·h / ml to about 2950 ng·h / ml. infIn some respects, methods for treating multiple myeloma in patients in need include administering to the patient an oral dose of 100 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides an in vivo plasma area under the curve (AUC) of about 2750 ng·h / ml to about 2950 ng·h / ml. infIn some respects, methods of treating multiple myeloma in patients in need include administering to the patient an oral dose of 100 mg of nirogasstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide), wherein the oral dose provides approximately 200 ng·h / ml, approximately 225 ng·h / ml, approximately 250 ng·h / ml, approximately 275 ng·h / ml, approximately 300 ng·h / ml, approximately 325 ng·h / ml, approximately 350 ng·h / ml, approximately 375 ng·h / ml, approximately 400 ng·h / ml, approximately 425 ng·h / ml, approximately 450 ng·h / ml, approximately 475 ng·h / ml, approximately 500 ng·h / ml, approximately 525 ng·h / ml, approximately 550 ng·h / ml, approximately 575 g. h / ml, approximately 600 ng·h / ml, approximately 625 ng·h / ml, approximately 675 ng·h / ml, approximately 700 ng·h / ml, approximately 725 ng·h / ml, approximately 750 ng·h / ml, approximately 775 ng·h / ml, approximately 800 ng·h / ml, approximately 825 ng·h / ml, approximately 850 ng·h / ml, approximately 875 ng·h / ml, approximately 900 ng·h / ml, approximately 925 ng·h / ml, approximately 950 ng·h / ml, approximately 975 ng·h / ml ml, approximately 1000 ng·h / ml, approximately 1025 ng·h / ml, approximately 1050 ng·h / ml, approximately 1075 ng·h / ml, approximately 1100 ng·h / ml, approximately 1125 ng·h / ml, approximately 1150 ng·h / ml, approximately 1175 ng·h / ml, approximately 1200 ng·h / ml, approximately 1225 ng·h / ml, approximately 1250 ng·h / ml, approximately 1275 ng·h / ml, approximately 1300 ng·h / ml, approximately 1325 ng·h / ml l, approximately 1350 ng·h / ml, approximately 1375 ng·h / ml, approximately 1400 ng·h / ml, approximately 1425 ng·h / ml, approximately 1450 ng·h / ml, approximately 1475 ng·h / ml, approximately 1500 ng·h / ml, approximately 1525 ng·h / ml, approximately 1550 ng·h / ml, approximately 1575 ng·h / ml, approximately 1600 ng·h / ml, approximately 1625 ng·h / ml, approximately 1650 ng·h / ml, approximately 1675 ng·h / ml Approximately 1700 ng·h / ml, approximately 1725 ng·h / ml, approximately 1750 ng·h / ml, approximately 1775 ng·h / ml, approximately 1800 ng·h / ml, approximately 1825 ng·h / ml, approximately 1850 ng·h / ml, approximately 1875 ng·h / ml, approximately 1900 ng·h / ml, approximately 1925 ng·h / ml, approximately 1950 ng·h / ml, approximately 2000 ng·h / ml, approximately 2025 ng·h / ml, approximately 2050 ng·h / mlApproximately 2100 ng·h / ml, approximately 2125 ng·h / ml, approximately 2150 ng·h / ml, approximately 2175 ng·h / ml, approximately 2200 ng·h / ml, approximately 2225 ng·h / ml, approximately 2250 ng·h / ml, approximately 2275 ng·h / ml, approximately 2300 ng·h / ml, approximately 2325 ng·h / ml, approximately 2550 ng·h / ml, approximately 2575 ng·h / ml, approximately 2600 ng·h / ml, approximately 2625 ng·h / ml The area under the in vivo plasma curve (AUC) at approximately 2650 ng·h / ml, approximately 2675 ng·h / ml, approximately 2700 ng·h / ml, approximately 2725 ng·h / ml, approximately 2750 ng·h / ml, approximately 2775 ng·h / ml, approximately 2800 ng·h / ml, approximately 2825 ng·h / ml, approximately 2850 ng·h / ml, approximately 2875 ng·h / ml, approximately 2900 ng·h / ml, approximately 2925 ng·h / ml, or approximately 2950 ng·h / ml. inf ).

[0201] In some aspects, methods of treating multiple myeloma include oral administration of nirogasat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide). In some aspects, methods of treating multiple myeloma include oral administration of nirogasat in solid dosage form or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide). In some aspects, the solid dosage form is a tablet or capsule.

[0202] In some aspects, methods of treating multiple myeloma include administering nirogalstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) once daily. In some aspects, methods of treating multiple myeloma include administering nirogalstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) twice daily. In some aspects, methods of treating multiple myeloma include administering nirogalstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) two, three, or four times daily. If nirogalstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) is administered more than once daily, the total daily dose for each administration may be the same or different. For example, if 100 mg of nirogalstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) is administered twice daily, the patient may receive two 50 mg doses (e.g., a 50 mg dose at 8 am and a 50 mg dose at 8 pm) or a 25 mg dose in the morning and a 75 mg dose in the evening. Each dose may also consist of more than one solid dosage form. For example, a single 50 mg dose (i.e., the morning dose of a total daily dose of 100 mg administered as two separate doses) can be administered as two 25 mg tablets.

[0203] In some aspects, methods of treating multiple myeloma include administering a single oral dose of nirogalstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) as concomitant therapy for multiple myeloma. In concomitant therapy for multiple myeloma, nirogalstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) is administered together with one or more additional active ingredients. In some aspects, concomitant therapy for multiple myeloma includes administering nirogalstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) in combination with BCMA therapy. In some aspects, BCMA-guided therapy includes one or more of allogeneic chimeric antigen receptor T-cell therapy, autologous chimeric antigen receptor T-cell therapy, immunotherapy (e.g., monoclonal antibody therapy), antibody-drug conjugate therapy, or bispecific antibody therapy with dual specificity for BCMA and immune-related targets (e.g., CD3). In other aspects, BCMA-guided therapy includes at least allogeneic chimeric antigen receptor T-cell therapy. In other respects, BCMA-guided therapy includes at least autologous chimeric antigen receptor T-cell therapy. In another respect, BCMA-guided therapy includes at least immunotherapy (e.g., monoclonal antibody therapy). In other respects, BCMA-guided therapy includes at least antibody-drug conjugate therapy. In other respects, BCMA-guided therapy includes at least bispecific antibody therapy with dual specificity for BCMA and immune-related targets (e.g., CD3). In some respects, methods for treating multiple myeloma include administering to a patient an oral dose of nirogasat or a pharmaceutically acceptable salt thereof in combination with mabetalumab.

[0204] In concomitant therapy for the treatment of multiple myeloma (e.g., in combination with mabetuzumab), nirogastart or its pharmaceutically acceptable salt (e.g., dihydrobromide form) is administered to the subject before, simultaneously with, or after administration of one or more other active ingredients (e.g., mabetuzumab).

[0205] In some respects, the treatment of multiple myeloma includes concomitant therapy with nirogasat or its pharmaceutically acceptable salts (e.g., dihydrobromide forms) and other active ingredients (e.g., mabetuzumab) as first-line therapy. In this respect, patients with multiple myeloma may have previously received and / or are currently receiving treatment for one or more unrelated diseases or conditions (e.g., anxiety disorders).

[0206] In some respects, treatment of multiple myeloma involves administering nirogalstat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) and BCMA-guided therapy (e.g., mabetalumab) to patients who have previously been treated for multiple myeloma. In some respects, patients with multiple myeloma have previously been treated with one or more of the following: proteasome inhibitors, immunomodulatory therapy, immunotherapy (e.g., monoclonal antibodies, such as monoclonal antibodies against CD38), stem cell transplantation, chemotherapy, targeted therapy (e.g., XPO1 inhibitors), or BCMA-guided therapy not in combination with nirogalstat.

[0207] In one aspect, nirogasat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) is administered orally to the subject, and BCMA-guided therapy (e.g., mabetumab) is administered intravenously or subcutaneously.

[0208] In some respects, patients with multiple myeloma have shown a complete response following administration of nirogalostat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) and BCMA-guided therapy (e.g., emabetuzumab). In some respects, patients with multiple myeloma have shown a near-complete response following administration of nirogalostat or a pharmaceutically acceptable salt thereof and BCMA-guided therapy (e.g., emabetuzumab). In some respects, patients with multiple myeloma have shown a strictly complete response following administration of nirogalostat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) and BCMA-guided therapy (e.g., emabetuzumab). In some respects, patients with multiple myeloma have shown a mild response following administration of nirogalostat or a pharmaceutically acceptable salt thereof (e.g., in the form of dihydrobromide) and BCMA-guided therapy (e.g., emabetuzumab). In some respects, patients with multiple myeloma have shown partial responses following administration of nirogasstat or its pharmaceutically acceptable salts (e.g., dihydrobromide) and BCMA-guided therapy (e.g., mabetuzumab). In some respects, patients with multiple myeloma have shown very good partial responses following administration of nirogasstat or its pharmaceutically acceptable salts (e.g., dihydrobromide) and BCMA-guided therapy (e.g., mabetuzumab). In some respects, patients with multiple myeloma have shown disease stability following administration of nirogasstat or its pharmaceutically acceptable salts (e.g., dihydrobromide) and BCMA-guided therapy (e.g., mabetuzumab).

[0209] Example

[0210] Example 1: Pharmacokinetics

[0211] The pharmacokinetic parameters for a single oral dose of nirogalstat dihydrobromide (PF-03084014) are provided in Tables 2A-2D below.

[0212] Table 2A

[0213]

[0214] Table 2B

[0215]

[0216] Table 2C

[0217]

[0218] Table 2D

[0219]

[0220]

[0221] The pharmacokinetic parameters of nirogalstat dihydrobromide at steady-state exposure for oral doses of 150 mg (free base equivalent) twice daily are provided in Table 2E below.

[0222] Table 2E

[0223]

[0224] Example 2: Nilogastricostat vs. placebo in patients with progressive desmoidoma / invasive fibromatosis (DT / A randomized, double-blind, placebo-controlled phase 3 trial in adult patients with AF.

[0225] A phase 3, double-blind, placebo-controlled study is underway to determine the efficacy and safety of nirogasta dihydrobromide in participants with progressive desmoidoma. Phase I studies in solid tumors provided preliminary efficacy (Messersmith, W. et al., "A Phase I, dose-finding study in patients with advanced solid malignancies of the oral γ-secretase inhibitor PF-03084014," Clin. Cancer Res., 21:60-7 (2015)), including long-term durable response and safety of nirogasta in participants with desmoid fibroma (Villalobos, VM et al., "Long-Term Follow-Up of Desmoid Fibroma Treated with PF-03084014, an Oral Gamma Secretase Inhibitor," Ann. Surg. Oncol., 25:768-75 (2018)). These encouraging results led to a Phase II study in participants with advanced desmoid fibroma (Kummar, S. et al., "Clinical Activity of the γ-Secretase Inhibitor PF-03084014 in Adults with Desmoid Tumors (Aggressive Fibromatosis), J. Clin. Oncol., 35:1561-69 (2017)). This study demonstrated that nirogalostatine resulted in a 29% response rate, significant tumor shrinkage as measured by magnetic resonance imaging (MRI), and no participants experienced disease progression during treatment. Importantly, participants in the responder group had previously failed systemic therapy (imatinib or sorafenib), indicating a need for alternative treatment options in this patient population. These results support further research on nirogalostatine in this population.

[0226] The objectives and endpoints are shown in Table 3.

[0227] Table 3

[0228]

[0229] Overall Design: The Phase 3 study will be a multicenter, randomized, double-blind, placebo-controlled, event-driven study to compare the efficacy, safety, and tolerability of nirogasat and placebo in adult participants with progressive DT / AF. The study will consist of two phases: a double-blind phase and an optional open-label extension (OLE) phase.

[0230] Once disease progression (confirmed by central review using RECIST v1.1) or a double-blind phase is completed (once the required number of events are observed and the primary PFS analysis is completed), treatment allocation for participants will be unblinded, and participants may have the option to join an optional OLE phase if eligible.

[0231] Participant types and disease characteristics:

[0232] 1. Participants had DT / AF and, within 12 months prior to the first dose of study treatment, had a progression ≥20% as measured by RECIST v1.1.

[0233] 2. Participants suffered from:

[0234] a. Newly diagnosed, measurable, progressive DT / AF that is not suitable for surgical resection or radiation therapy;

[0235] or

[0236] b. Progressive DT / AF that relapses after initial treatment for CR;

[0237] or

[0238] c. Pre-existing DT / AF, previously treated and with residual tumor progression.

[0239] 3. Participants agree to provide archived or new tumor tissue for confirmation of the disease.

[0240] 4. If a participant has previously received an investigational therapy for the treatment of DT / AF, the participant must have completed the previous therapy at least 28 days prior to signing the informed consent form. All toxicities from the previous treatment must have decreased to ≤ grade 1 or baseline.

[0241] 5. Currently receiving nonsteroidal anti-inflammatory drug (NSAID) treatment. No Participants with DT / AF disease must have received NSAID treatment before observed progression (inclusion criterion 1):

[0242] a. Long-term plan for daily use (defined as stable for 28 days prior to signing the informed consent form); or

[0243] b. Occasionally (defined as ≤3 days per week) for the treatment of pain or as an anti-inflammatory agent in permitted conditions such as headaches, arthritis, etc.

[0244] c. Participants had an Eastern Cooperative Oncology Group (ECOG) performance status ≤2 at the time of screening.

[0245] 6. Participants have adequate organ and bone marrow function, as defined by the following screening laboratory values:

[0246] a. Absolute neutrophil count ≥1500 / μL;

[0247] b. Platelet count ≥100×10 3 / μL;

[0248] c. Hemoglobin ≥ 9 g / dL;

[0249] d. Total bilirubin ≤ 1.5 × Upper Limit of Normal (ULN) (If bilirubin is graded and direct bilirubin < 35%, then separated bilirubin > 1.5 x ULN is acceptable);

[0250] e. Aspartate aminotransferase (AST) (serum AST) / alanine aminotransferase (ALT) (serum ALT) ≤ 2 × ULN; and

[0251] f. If creatinine is ≤1.5×ULN, or if creatinine is >1.5×ULN, the calculated creatinine clearance should be ≥60 mL / min / 1.73 m 2 (Using the Cockcroft-Gault formula);

[0252] g. Participants were able to swallow the tablets and had no gastrointestinal conditions that affected absorption.

[0253] Figure 1 The protocol for this Phase 3 clinical trial was provided.

[0254] Research on treatment

[0255] Participants received (1) three 50 mg nirogalstat tablets twice daily (i.e., 150 mg nirogalstat twice daily for a total daily dose of 300 mg nirogalstat) or (2) three placebo tablets twice daily. Nirogalstat in the tablets was in the form of its dihydrobromide salt.

[0256] Because inhibition of CYP3A4 isoenzymes can increase nirogalstat exposure, potentially leading to increased toxicity, the use of known strong / moderate CYP3A4 inhibitors is not permitted. When a strong CYP3A4 inducer is administered, it may induce nirogalstat metabolism. Therefore, co-administration of nirogalstat with a strong CYP3A4 inducer is not permitted.

[0257] Co-administration of gastric acid inhibitors such as proton pump inhibitors (e.g., omeprazole, esomeprazole, and lansoprazole) may reduce the absorption of nirogastine. If possible, these medications should be avoided, or if necessary, they should be administered 2 to 4 hours after the morning dose of the study treatment.

[0258] Modify or interrupt the dosage as described in the table below.

[0259]

[0260]

[0261] 1 NCI CTCAE refers to the National Cancer Institute's Common Terminology Standard for Adverse Events, version 5.0.

[0262] 2 For events of premature menopause / primary ovarian insufficiency, dose reduction is not required; however, for symptomatic participants, dose reduction may be considered based on individual benefit / risk profiles. For reproductive toxicity, dose interruption is not required before dose reduction.

[0263] The most common adverse reactions requiring dose reduction or interruption are diarrhea, maculopapular rash, hypophosphatemia, stomatitis, folliculitis, and fatigue.

[0264] The trial met its primary endpoint of improved progression-free survival (PFS), demonstrating a highly statistically and clinically significant improvement of nirogasat compared to placebo, with a meaningful reduction in the risk of disease progression (p<0.001, hazard ratio (HR) = 0.29). In addition to meeting the primary endpoint, the trial also met all key secondary endpoints, with nirogasat demonstrating statistically significant improvements in objective response rate (ORR) and four different quality of life (QoL) assessments and patient-reported outcomes (PROs) (p<0.001 for each). Data in Figures 3 to 8 The description of the clinical study and results is also available in Gounder et al., N Engl J Med 2023, 388:898-912 (DOI:10.1056 / NEJMoa2210140), which is hereby incorporated in its entirety by reference.

[0265] The primary outcome measure was the number of progression-free survival events, defined as the time from randomization to the date of assessment of progression or death. Key secondary and exploratory measures included the incidence of adverse events of toxicity graded according to the National Cancer Institute's Common Terminology for Adverse Events (CTSA); ORR using RECIST 1.1 criteria; DOR in participants with a best response of CR or PR (not in the test tier); and change in tumor volume relative to baseline as measured by MRI volumetrics (exploratory). PRO assessments included the Gounder / Desmoid Tumor Research Tumor Foundation (DTRF) Desmoid Tumor Symptom Scale (GODDESS) (time range: daily from the last 7 days of each cycle [28 days / cycle] to study completion); the BPI Short Form (daily from the last 7 days of each cycle); the PROMIS PF Short Form + 3 additional items a (last day of each cycle); and the EORTC QLQ-C30 (last day of each cycle). Table 4 provides the mean change in EORTC relative to baseline.

[0266] Table 4

[0267]

[0268] Note: Positive changes relative to baseline indicate symptom improvement, while negative changes relative to baseline indicate symptom worsening. A positive least squares (LS) mean difference (between nirogalstat and placebo) supports the superiority of nirogalstat over placebo.

[0269] Example 3: Nilogasstat in patients with symptomatic desmoidoma / invasive fibromatosis

[0270] (DT / AF) placebo-controlled phase 3 trial in adults

[0271] A multicenter, randomized, double-blind, placebo-controlled phase 3 study will be conducted to compare the efficacy, safety, and tolerability of nirogasat and placebo in adult participants with uncontrollable pain due to DT / AF. The study will consist of two phases: a double-blind phase and an optional open-label extension (OLE) phase for eligible participants.

[0272] Participants will be screened up to 28 days before the first dose of the study treatment, and eligibility will be determined based on inclusion and exclusion criteria. During the screening period, potential participants will also be screened to determine their willingness to record pain and medication usage daily for 12 weeks.

[0273] During the screening period, participants were asked to keep daily records of their pain and analgesic use to calculate their weekly mean pain intensity (API) and mean analgesic use (AAU). Only participants with uncontrollable tumor-related pain defined as API > 4 for at least two consecutive weeks were randomly assigned to the study.

[0274] Following all pre-randomization / pre-dose assessments on Day 1 of Cycle 1, eligible participants will be randomized (1:1) to receive the study treatment (nirogalostat or placebo). After the first dose of the study treatment, participants will return to the outpatient clinic for scheduled study visits at Cycle 1 (Day 15), Cycle 2 (Days 1 and 15), Cycle 3 (Days 1 and 15), End of Study (EOS) (14 days after Day 15 of Cycle 3), and Follow-up (30 days after the last dose of the study treatment, if the participant has not entered the OLE phase).

[0275] During the 12-week study treatment period, participants were required to record their daily pain scores, analgesic use, and study treatment dosage on an electronic device (eDiary). Daily reminders were provided via electronic devices and / or telephones to ensure strict adherence to the data collection procedures for pain and medication use. The patients' daily pain scores and medication lists were reviewed during scheduled study outpatient visits. In addition, health status data were collected using the European Five-Dimensional Quality of Life Scale (“EQ-5D”), the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (“EORTC QLQ-C30”), the Patient Global Impression Change Scale (“PGI-C”), the Patient Global Impression Severity Scale (“PGI-S”), and the Short Form Pain Scale (“BPI-SF”).

[0276] Upon completion of the study, participants will return to the research center for an EOS visit (approximately 14 days after day 15 of cycle 3). During the EOS visit, eligible participants may choose to join an optional OLE phase.

[0277] Participants who terminate their study treatment prematurely for any reason should return to the research center as soon as possible to complete the End of Treatment (“EOT”) visit before or as close as possible to the last dose of study treatment, and will not be eligible to join the optional OLE phase.

[0278] Figure 2 The protocol for this Phase 3 clinical trial was provided.

[0279] Example 4: Multiple myeloma

[0280] The aim of this study was to evaluate the safety and efficacy of nirogasat in combination with agents targeting B-cell maturation antigen (BCMA) (e.g., antibody-drug conjugates (ADCs), bispecific antibodies, CAR-T therapy, or monoclonal antibodies) in adults with relapsed or refractory multiple myeloma.

[0281] Measurable endpoints may include

[0282] • DE stage: The number of participants who achieved ORR (according to the International Myeloma Working Group "IMWG" response criteria, ORR is defined as the percentage of participants with PR or better response).

[0283] • CE stage: Number of participants who achieved clinical benefit rate (CBR) (CBR is defined as the percentage of participants with advanced or metastatic cancer who achieved a complete response, partial response, or stable disease in response to a therapeutic intervention in a clinical trial of an anticancer agent).

[0284] • DE and CE phases: Number of participants who achieved a partial response (“PR”): The number of participants with PR will be analyzed according to the IMWG criteria.

[0285] • DE and CE phases: Number of participants achieving a very good partial response (“VGPR”): The number of participants with VGPR according to the IMWG criteria will be analyzed.

[0286] • DE and CE phases: Number of participants who achieved a complete response (CR): Participants with CR according to IMWG criteria will be analyzed.

[0287] • DE and CE phases: Nilogasstat concentration when used in combination with a second agent: Blood samples were collected to determine the concentration of nilogasstat.

[0288] • CE stage: The number of participants who achieved progression-free survival (PFS) (PFS is defined as the time from randomization to the earliest date of disease progression (PD) confirmed by IMWG or death from any cause).

[0289] • CE phase: Duration of response (DoR) (DoR is defined as the time from the first documented evidence or PR or better response to the time when a participant who has achieved a confirmed partial response or better response dies due to disease progression according to IMWG).

[0290] • CE phase: Time to Response (TTR) (TTR is defined as the time between the randomization date and the first recorded evidence of response (PR or better response) in participants who have reached a response (confirmed PR or better response).

[0291] • CE phase: The number of participants who reach overall survival (OS) (OS is defined as the time from randomization to death from any cause).

[0292] Additional endpoints may include

[0293] • Overall Response Rate (ORR) (ORR is defined as the proportion of participants who achieve a partial response (PR) or better according to the IMWG 2016 criteria).

[0294] • Very good partial response (VGPR) or better response rate (VGPR or better response rate is defined as the proportion of participants who achieve VGPR or better response (strict full response (“sCR”) + full response (“CR”) + VGPR) according to the IMWG2016 criteria).

[0295] • Complete Response (CR) or better response rate (CR or better response rate is defined as the proportion of participants who achieve CR or better response (sCR+CR) according to the IMWG 2016 criteria).

[0296] • Strict full response (sCR) rate (sCR rate is defined as the proportion of participants who achieve sCR according to the IMWG 2016 criteria).

[0297] • Response duration (according to the IMWG 2016 standard, response duration is defined as the time from the date of initial recording of the response (PR or better response) to the date of first recording of evidence of disease progression (PD).

[0298] • Time to reach response (Time to reach response is defined as the time between the date of first administration of study treatment and the first efficacy evaluation in which the participant meets all criteria for PR or better response).

[0299] Selection criteria may include:

[0300] • A recorded diagnosis of relapsed / refractory multiple myeloma (“MM”) with measurable disease (serum, urine, or free light chains (“FLC”)) according to IMWG criteria.

[0301] • Patients who have received at least three lines of MM therapy, including proteasome inhibitors, immunomodulators, and anti-CD38 antibodies (unless contraindicated), and are refractory to last-line therapy.

[0302] • Eastern Cooperative Oncology Group (“ECOG”) is 0 or 1

[0303] • No donor (product) specific anti-HLA antibodies

[0304] • Participants with an ECOG physical status of 0-1, unless ECOG less than or equal to 2 is solely attributable to skeletal complications and / or skeletal pain caused by MM.

[0305] • Participants with measurable disease were defined as having at least one of the following: serum M-protein greater than or equal to 0.5 g / dL (>=5 g / L), or urinary M-protein greater than or equal to 200 mg / 24 hours, or serum free light chain (“FLC”) assay: FLC level involved greater than or equal to 10 mg / dL (>=100 mg / L) and abnormal serum FLC ratio (<0.26 or >1.65).

[0306] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference in their entirety as if each individual publication, patent, or patent application were specifically and individually indicated to be incorporated herein by reference in its entirety. Where a term in this application is found to have a different definition in a document incorporated herein by reference, the definition provided herein shall be used as the definition of that term.

[0307] While the invention has been described in conjunction with specific aspects thereof, it should be understood that further modifications are possible and that this application is intended to cover any variations, uses or modifications that generally follow these principles, including such deviations from this disclosure within the known or customary practice in the field to which this invention pertains, and applicable to the essential features set forth above and followed within the scope of the claims.

Claims

1. A method for treating a desmoid tumor in a patient in need thereof, the method comprising orally administering to the patient 150 mg (free base equivalent dose) of nirogasistat or a pharmaceutically acceptable salt thereof twice daily, wherein the method comprises one or more of the following: (a) when the patient still develops Grade 3 diarrhea lasting for at least 3 days after receiving maximum drug therapy, suspending the administration of the nirogasistat or its pharmaceutically acceptable salt until the diarrhea subsides to no higher than Grade 1 diarrhea or baseline, and then restarting oral administration of the nirogasistat or its pharmaceutically acceptable salt at a dose of 100 mg (free base equivalent dose) twice a day; (b) when the patient develops grade 3 folliculitis, suspending the administration of the nirogasistat or its pharmaceutically acceptable salt until the folliculitis subsides to no higher than grade 1 folliculitis or baseline, and then restarting oral administration of the nirogasistat or its pharmaceutically acceptable salt at a dose of 100 mg (free base equivalent dose) twice a day; (c) when the patient develops a grade 3 maculopapular rash, suspending the administration of the nirogasistat or a pharmaceutically acceptable salt thereof until the maculopapular rash subsides to no higher than grade 1 maculopapular rash or baseline, and then restarting oral administration of the nirogasistat or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice a day; (d) when the patient develops Grade 3 hidradenitis, suspending the administration of the nilegastrostat or its pharmaceutically acceptable salt until the hidradenitis subsides to no higher than Grade 1 hidradenitis or baseline, and then restarting oral administration of the nilegastrostat or its pharmaceutically acceptable salt twice daily at a dose of 100 mg (free base equivalent dose); (e) when the patient develops Grade 3 hypophosphatemia that persists for at least 7 days after receiving maximum replacement therapy, suspending the administration of the nirogasistat or its pharmaceutically acceptable salt until the hypophosphatemia resolves to no higher than Grade 1 hypophosphatemia or baseline, and then restarting oral administration of the nirogasistat or its pharmaceutically acceptable salt at a dose of 100 mg (free base equivalent dose) twice a day; (f) when the patient still develops Grade 3 hypokalemia after receiving maximum replacement therapy, suspending the administration of the nirogasistat or its pharmaceutically acceptable salt until the hypokalemia resolves to no higher than Grade 1 hypokalemia or baseline, and then restarting oral administration of the nirogasistat or its pharmaceutically acceptable salt at a dose of 100 mg (free base equivalent dose) twice a day; and (g) When the patient develops alanine aminotransferase (ALT) or aspartate aminotransferase (AST) of 3 to 5 times the upper limit of normal (ULN), the administration of the nirogasistat or its pharmaceutically acceptable salt is suspended until the ALT, AST or both subside to no higher than 3 times the ULN or baseline, and then the oral administration of the nirogasistat or its pharmaceutically acceptable salt is resumed at a dose of 100 mg (free base equivalent dose) twice a day.

2. The method of claim 1, further comprising one or more of the following: (h) when the patient develops ALT or AST greater than 5 times ULN, permanently discontinue the treatment with nirogasistat or a pharmaceutically acceptable salt thereof; (i) when the patient develops anaphylactic shock or other severe hypersensitivity reactions, permanently terminate the treatment with nirogasistat or its pharmaceutically acceptable salt; and (j) for another serious adverse reaction or in the case of a life-threatening adverse reaction, withhold the administration of the nirogasistat or its pharmaceutically acceptable salt until the adverse reaction resolves to no higher than Grade 1 adverse reaction or baseline, and then, after careful consideration of the potential benefit and the possibility of recurrence of the adverse reaction, (A) restart oral administration of the nirogasistat or its pharmaceutically acceptable salt at a dose of 100 mg (free base equivalent dose) twice daily, and (B) permanently discontinue treatment with the nirogasistat or its pharmaceutically acceptable salt upon recurrence of a severe or life-threatening adverse reaction at a dose of 100 mg (free base equivalent dose) twice daily.

3. The method according to claim 1 or 2, wherein the method comprises (a) when the patient still develops grade 3 diarrhea lasting for at least 3 days after receiving maximum drug therapy, suspending the administration of the nirogasistat or its pharmaceutically acceptable salt until the diarrhea subsides to no higher than grade 1 diarrhea or baseline, and then resuming oral administration of the nirogasistat or its pharmaceutically acceptable salt at a dose of 100 mg (free base equivalent dose) twice a day.

4. The method according to any one of the preceding claims, wherein the method comprises (b) when the patient develops Grade 3 folliculitis, suspending the administration of the nirogasistat or a pharmaceutically acceptable salt thereof until the folliculitis resolves to no higher than Grade 1 folliculitis or baseline, and then resuming oral administration of the nirogasistat or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice daily.

5. The method according to any one of the preceding claims, wherein the method comprises (c) when the patient develops a grade 3 maculopapular rash, suspending the administration of the nirogasistat or a pharmaceutically acceptable salt thereof until the maculopapular rash resolves to no higher than grade 1 maculopapular rash or baseline, and then resuming oral administration of the nirogasistat or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice daily.

6. The method of any one of the preceding claims, wherein the method comprises (d) when the patient develops Grade 3 hidradenitis, suspending the administration of the nilegastat or a pharmaceutically acceptable salt thereof until the hidradenitis resolves to no higher than Grade 1 hidradenitis or baseline, and then resuming oral administration of the nilegastat or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice daily.

7. The method of any one of the preceding claims, wherein the method comprises (e) when the patient develops Grade 3 hypophosphatemia that persists for at least 7 days after receiving maximum replacement therapy, suspending the administration of the nirogasistat or a pharmaceutically acceptable salt thereof until the hypophosphatemia resolves to no higher than Grade 1 hypophosphatemia or baseline, and then resuming oral administration of the nirogasistat or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice daily.

8. The method according to any one of the preceding claims, wherein the method comprises (f) when the patient still develops Grade 3 hypokalemia after receiving maximum replacement therapy, suspending the administration of the nirogasistat or a pharmaceutically acceptable salt thereof until the hypokalemia resolves to no higher than Grade 1 hypokalemia or baseline, and then resuming oral administration of the nirogasistat or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice daily.

9. The method of any one of the preceding claims, wherein the method comprises (g) when the patient develops ALT or AST of 3 to 5 times ULN, suspending the administration of the nirogasistat or a pharmaceutically acceptable salt thereof until the ALT, AST or both resolve to no greater than 3 times ULN or baseline, and then resuming oral administration of the nirogasistat or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice daily.

10. The method of any one of the preceding claims, wherein the method comprises (h) permanently discontinuing the treatment with nirogasistat or a pharmaceutically acceptable salt thereof when the patient develops ALT or AST greater than 5 times ULN.

11. The method of any one of the preceding claims, wherein the method comprises (i) permanently terminating the treatment with nirogasistat or a pharmaceutically acceptable salt thereof when the patient develops anaphylactic shock or other severe hypersensitivity reaction.

12. The method according to any one of the preceding claims, wherein the method comprises: (a) when the patient still develops Grade 3 diarrhea lasting for at least 3 days after receiving maximum drug therapy, suspending the administration of the nirogasistat or its pharmaceutically acceptable salt until the diarrhea subsides to no higher than Grade 1 diarrhea or baseline, and then restarting oral administration of the nirogasistat or its pharmaceutically acceptable salt at a dose of 100 mg (free base equivalent dose) twice a day; (b) when the patient develops grade 3 folliculitis, suspending the administration of the nirogasistat or its pharmaceutically acceptable salt until the folliculitis subsides to no higher than grade 1 folliculitis or baseline, and then restarting oral administration of the nirogasistat or its pharmaceutically acceptable salt at a dose of 100 mg (free base equivalent dose) twice a day; (c) when the patient develops a grade 3 maculopapular rash, suspending the administration of the nirogasistat or a pharmaceutically acceptable salt thereof until the maculopapular rash subsides to no higher than grade 1 maculopapular rash or baseline, and then restarting oral administration of the nirogasistat or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice a day; (d) when the patient develops Grade 3 hidradenitis, suspending the administration of the nilegastrostat or its pharmaceutically acceptable salt until the hidradenitis subsides to no higher than Grade 1 hidradenitis or baseline, and then restarting oral administration of the nilegastrostat or its pharmaceutically acceptable salt twice daily at a dose of 100 mg (free base equivalent dose); (e) when the patient develops Grade 3 hypophosphatemia that persists for at least 7 days after receiving maximum replacement therapy, suspending the administration of the nirogasistat or its pharmaceutically acceptable salt until the hypophosphatemia resolves to no higher than Grade 1 hypophosphatemia or baseline, and then restarting oral administration of the nirogasistat or its pharmaceutically acceptable salt at a dose of 100 mg (free base equivalent dose) twice a day; (f) when the patient still develops Grade 3 hypokalemia after receiving maximum replacement therapy, suspending the administration of the nirogasistat or its pharmaceutically acceptable salt until the hypokalemia resolves to no higher than Grade 1 hypokalemia or baseline, and then restarting oral administration of the nirogasistat or its pharmaceutically acceptable salt at a dose of 100 mg (free base equivalent dose) twice a day; and (g) When the patient develops ALT or AST of 3 to 5 times ULN, suspending the administration of the nirogasistat or its pharmaceutically acceptable salt until the ALT, AST or both subside to no higher than 3 times ULN or baseline, and then restarting oral administration of the nirogasistat or its pharmaceutically acceptable salt twice a day at a dose of 100 mg (free base equivalent dose).

13. The method of claim 1, wherein the method comprises: (a) when the patient still develops Grade 3 diarrhea lasting for at least 3 days after receiving maximum drug therapy, suspending the administration of the nirogasistat or its pharmaceutically acceptable salt until the diarrhea subsides to no higher than Grade 1 diarrhea or baseline, and then restarting oral administration of the nirogasistat or its pharmaceutically acceptable salt at a dose of 100 mg (free base equivalent dose) twice a day; (b) when the patient develops grade 3 folliculitis, suspending the administration of the nirogasistat or its pharmaceutically acceptable salt until the folliculitis subsides to no higher than grade 1 folliculitis or baseline, and then restarting oral administration of the nirogasistat or its pharmaceutically acceptable salt at a dose of 100 mg (free base equivalent dose) twice a day; (c) when the patient develops a grade 3 maculopapular rash, suspending the administration of the nirogasistat or a pharmaceutically acceptable salt thereof until the maculopapular rash subsides to no higher than grade 1 maculopapular rash or baseline, and then restarting oral administration of the nirogasistat or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice a day; (d) when the patient develops Grade 3 hidradenitis, suspending the administration of the nilegastrostat or its pharmaceutically acceptable salt until the hidradenitis subsides to no higher than Grade 1 hidradenitis or baseline, and then restarting oral administration of the nilegastrostat or its pharmaceutically acceptable salt twice daily at a dose of 100 mg (free base equivalent dose); (e) when the patient develops Grade 3 hypophosphatemia that persists for at least 7 days after receiving maximum replacement therapy, suspending the administration of the nirogasistat or its pharmaceutically acceptable salt until the hypophosphatemia resolves to no higher than Grade 1 hypophosphatemia or baseline, and then restarting oral administration of the nirogasistat or its pharmaceutically acceptable salt at a dose of 100 mg (free base equivalent dose) twice a day; (f) when the patient still develops Grade 3 hypokalemia after receiving maximum replacement therapy, suspending the administration of the nirogasistat or its pharmaceutically acceptable salt until the hypokalemia subsides to no higher than Grade 1 hypokalemia or baseline, and then restarting oral administration of the nirogasistat or its pharmaceutically acceptable salt at a dose of 100 mg (free base equivalent dose) twice a day; (g) when the patient develops ALT or AST of 3 to 5 times ULN, suspending the administration of the nirogasistat or its pharmaceutically acceptable salt until the ALT, AST or both subside to no higher than 3 times ULN or baseline, and then restarting oral administration of the nirogasistat or its pharmaceutically acceptable salt twice daily at a dose of 100 mg (free base equivalent dose); (h) when the patient develops ALT or AST greater than 5 times ULN, permanently discontinue the treatment with nirogasistat or a pharmaceutically acceptable salt thereof; (i) when the patient develops anaphylactic shock or other severe hypersensitivity reactions, permanently terminate the treatment with nirogasistat or its pharmaceutically acceptable salt; and (j) for another serious adverse reaction or in the case of a life-threatening adverse reaction, withhold the administration of the nirogasistat or its pharmaceutically acceptable salt until the adverse reaction resolves to no higher than Grade 1 adverse reaction or baseline, and then, after careful consideration of the potential benefit and the possibility of recurrence of the adverse reaction, (A) restart oral administration of the nirogasistat or its pharmaceutically acceptable salt at a dose of 100 mg (free base equivalent dose) twice daily, and (B) permanently discontinue treatment with the nirogasistat or its pharmaceutically acceptable salt upon recurrence of a severe or life-threatening adverse reaction at a dose of 100 mg (free base equivalent dose) twice daily.

14. The method according to any one of the preceding claims, wherein when the patient develops a grade 3 dermatological reaction, the administration of the nirogasistat or a pharmaceutically acceptable salt thereof is suspended until the dermatological reaction subsides to no higher than grade 1 dermatological reaction or baseline, and then oral administration of the nirogasistat or a pharmaceutically acceptable salt thereof is resumed at a dose of 100 mg (free base equivalent dose) twice daily.

15. The method of any of the preceding claims, wherein the patient has a mutation in the adenomatous polyposis coli (APC) tumor suppressor gene.

16. The method of any of the preceding claims, wherein the patient has a mutation in the CTNNB1 (β-catenin) gene.

17. The method of any of the preceding claims, wherein the patient has previously been treated with a tyrosine kinase inhibitor.

18. The method of any of the preceding claims, wherein the patient has an intra-abdominal tumor.

19. The method of any one of the preceding claims, wherein the patient is an adult.

20. The method of any of the preceding claims, wherein the patient has a family history of familial adenomatous polyposis.

21. The method of any of the preceding claims, wherein the patient has refractory or relapsed disease following prior treatment.

22. The method of any one of the preceding claims, wherein the patient is a treatment naive patient.

23. The method of any one of the preceding claims, wherein the patient is a postmenopausal woman.

24. The method of any one of the preceding claims, wherein a gastric acid inhibitor is avoided or administered 4 hours after administration of the nirogasistat or a pharmaceutically acceptable salt thereof.

25. A method for treating desmoid tumors in a patient with a family history of familial adenomatous polyposis, the method comprising orally administering to the patient 150 mg (free base equivalent dose) of nirogasistat or a pharmaceutically acceptable salt thereof twice daily.

26. A method for treating desmoid tumors in a treatment-naive patient, the method comprising orally administering to the patient 150 mg (free base equivalent dose) of nirogasistat or a pharmaceutically acceptable salt thereof twice daily.

27. The method of any one of the preceding claims, wherein the nirogasistat or a pharmaceutically acceptable salt thereof is nirogasistat dihydrobromide.

28. The method of any of the preceding claims, wherein the patient exhibits a nirogasistat C of about 480 to about 950 ng / mL following an initial administration of 150 mg (free base equivalent dose) of nirogasistat or a pharmaceutically acceptable salt thereof. max .

29. The method of any of the preceding claims, wherein after an initial administration of 150 mg (free base equivalent dose) of nirogasistat or a pharmaceutically acceptable salt thereof, the patient exhibits a nirogasistat C of about 550 to about 1100 ng / mL. max .

30. The method of claim 29, wherein after an initial administration of 150 mg (free base equivalent dose) of nirogasistat or a pharmaceutically acceptable salt thereof, the patient exhibits a nirogasistat C of about 600 to about 800 ng / mL. max .

31. The method of any of the preceding claims, wherein the patient exhibits a nirogasistat AUC of less than 4000 ng·h / mL following an initial administration of 150 mg (free base equivalent dose) of nirogasistat or a pharmaceutically acceptable salt thereof. last .

32. The method of any of the preceding claims, wherein after an initial administration of 150 mg (free base equivalent dose) of nirogasistat or a pharmaceutically acceptable salt thereof, the patient exhibits a nirogasistat AUC of about 2000 to about 4000 ng·h / mL. last .

33. The method of any of the preceding claims, wherein the patient exhibits an AUC of about 2200 to about 4800 ng·h / mL for nirogasistat following an initial administration of 150 mg (free base equivalent dose) of nirogasistat or a pharmaceutically acceptable salt thereof. inf .

34. The method of claim 33, wherein after an initial administration of 150 mg (free base equivalent dose) of nirogasistat or a pharmaceutically acceptable salt thereof, the patient exhibits an AUC of nirogasistat of about 2200 to about 3300 ng·h / mL. inf .

35. The method of any of the preceding claims, wherein the patient exhibits a nilocistat C of about 1000 to 1500 ng / mL at steady-state exposure of 150 mg (free base equivalent dose) of nilocistat or a pharmaceutically acceptable salt thereof twice daily. max .

36. The method of claim 35, wherein the patient exhibits a nilocistat C of about 1100 to about 1400 ng / mL at steady-state exposure of 150 mg (free base equivalent dose) of nilocistat or a pharmaceutically acceptable salt thereof twice daily. max .

37. The method of any of the preceding claims, wherein the patient exhibits a nilocistat AUC of about 5000 to about 8000 ng·h / mL at steady-state exposure of 150 mg (free base equivalent dose) of nilocistat or a pharmaceutically acceptable salt thereof administered twice daily. tau .

38. The method of claim 37, wherein the patient exhibits a nilocistat AUC of about 6000 to about 7000 ng·h / mL at steady-state exposure of 150 mg (free base equivalent dose) of nilocistat or a pharmaceutically acceptable salt thereof administered twice daily. tau .

39. A method for treating multiple myeloma in a patient in need thereof, the method comprising administering to the patient simultaneously (i) nirogasistat or a pharmaceutically acceptable salt thereof and (ii) one or more additional active ingredients for treating multiple myeloma, wherein the method comprises (A) orally administering to the patient 150 mg (free base equivalent dose) of nirogasistat or a pharmaceutically acceptable salt thereof twice daily and (B) one or more of the following: (a) when the patient still develops Grade 3 diarrhea lasting for at least 3 days after receiving maximum drug therapy, suspending the administration of the nirogasistat or its pharmaceutically acceptable salt until the diarrhea subsides to no higher than Grade 1 diarrhea or baseline, and then restarting oral administration of the nirogasistat or its pharmaceutically acceptable salt at a dose of 100 mg (free base equivalent dose) twice a day; (b) when the patient develops grade 3 folliculitis, suspending the administration of the nirogasistat or its pharmaceutically acceptable salt until the folliculitis subsides to no higher than grade 1 folliculitis or baseline, and then restarting oral administration of the nirogasistat or its pharmaceutically acceptable salt at a dose of 100 mg (free base equivalent dose) twice a day; (c) when the patient develops a grade 3 maculopapular rash, suspending the administration of the nirogasistat or a pharmaceutically acceptable salt thereof until the maculopapular rash subsides to no higher than grade 1 maculopapular rash or baseline, and then restarting oral administration of the nirogasistat or a pharmaceutically acceptable salt thereof at a dose of 100 mg (free base equivalent dose) twice a day; (d) when the patient develops Grade 3 hidradenitis, suspending the administration of the nilegastrostat or its pharmaceutically acceptable salt until the hidradenitis subsides to no higher than Grade 1 hidradenitis or baseline, and then restarting oral administration of the nilegastrostat or its pharmaceutically acceptable salt twice daily at a dose of 100 mg (free base equivalent dose); (e) when the patient develops Grade 3 hypophosphatemia that persists for at least 7 days after receiving maximum replacement therapy, suspending the administration of the nirogasistat or its pharmaceutically acceptable salt until the hypophosphatemia resolves to no higher than Grade 1 hypophosphatemia or baseline, and then restarting oral administration of the nirogasistat or its pharmaceutically acceptable salt at a dose of 100 mg (free base equivalent dose) twice a day; (f) when the patient still develops Grade 3 hypokalemia after receiving maximum replacement therapy, suspending the administration of the nirogasistat or its pharmaceutically acceptable salt until the hypokalemia resolves to no higher than Grade 1 hypokalemia or baseline, and then restarting oral administration of the nirogasistat or its pharmaceutically acceptable salt at a dose of 100 mg (free base equivalent dose) twice a day; and (g) When the patient develops alanine aminotransferase (ALT) or aspartate aminotransferase (AST) of 3 to 5 times the upper limit of normal (ULN), the administration of the nirogasistat or its pharmaceutically acceptable salt is suspended until the ALT, AST or both subside to no higher than 3 times the ULN or baseline, and then the oral administration of the nirogasistat or its pharmaceutically acceptable salt is resumed at a dose of 100 mg (free base equivalent dose) twice a day.

40. The method of claim 39, wherein the patient is concurrently administered BCMA therapy.

41. The method of claim 39 or 40, further comprising one or more of the following: (h) when the patient develops ALT or AST greater than 5 times ULN, permanently discontinue the treatment with nirogasistat or a pharmaceutically acceptable salt thereof; (i) when the patient develops anaphylactic shock or other severe hypersensitivity reactions, permanently terminate the treatment with nirogasistat or its pharmaceutically acceptable salt; and (j) for another serious adverse reaction or in the case of a life-threatening adverse reaction, withhold the administration of the nirogasistat or its pharmaceutically acceptable salt until the adverse reaction resolves to no higher than Grade 1 adverse reaction or baseline, and then, after careful consideration of the potential benefit and the possibility of recurrence of the adverse reaction, (A) restart oral administration of the nirogasistat or its pharmaceutically acceptable salt at a dose of 100 mg (free base equivalent dose) twice daily, and (B) permanently discontinue treatment with the nirogasistat or its pharmaceutically acceptable salt upon recurrence of a severe or life-threatening adverse reaction at a dose of 100 mg (free base equivalent dose) twice daily.

42. A method for treating multiple myeloma in a patient in need thereof, the method comprising administering to the patient simultaneously (i) nirogasistat or a pharmaceutically acceptable salt thereof and (ii) one or more additional active ingredients for treating multiple myeloma, wherein the method comprises (A) orally administering to the patient twice daily 100 mg (free base equivalent dose) of nirogasistat or a pharmaceutically acceptable salt thereof and (B) one or more of the following: (a) when the patient still has grade 3 diarrhea lasting for at least 3 days after receiving maximum drug therapy, suspend the administration of nirogasistat or its pharmaceutically acceptable salt until the diarrhea subsides to no higher than grade 1 diarrhea or baseline, and then restart the oral administration of nirogasistat or its pharmaceutically acceptable salt twice a day at a dose of 50 mg (free base equivalent dose); (b) when the patient develops grade 3 folliculitis, suspending the administration of the nirogasistat or its pharmaceutically acceptable salt until the folliculitis subsides to no higher than grade 1 folliculitis or baseline, and then restarting oral administration of the nirogasistat or its pharmaceutically acceptable salt twice a day at a dose of 50 mg (free base equivalent dose); (c) when the patient develops grade 3 maculopapular rash, suspending the administration of the nirogasistat or its pharmaceutically acceptable salt until the maculopapular rash subsides to no higher than grade 1 maculopapular rash or baseline, and then restarting oral administration of the nirogasistat or its pharmaceutically acceptable salt at a dose of 50 mg (free base equivalent dose) twice a day; (d) when the patient develops Grade 3 hidradenitis, suspending the administration of the nilegastrostat or its pharmaceutically acceptable salt until the hidradenitis subsides to no higher than Grade 1 hidradenitis or baseline, and then restarting oral administration of the nilegastrostat or its pharmaceutically acceptable salt twice daily at a dose of 50 mg (free base equivalent dose); (e) when the patient still develops Grade 3 hypophosphatemia lasting for at least 7 days after receiving maximum replacement therapy, suspending the administration of the nirogasistat or its pharmaceutically acceptable salt until the hypophosphatemia subsides to no higher than Grade 1 hypophosphatemia or baseline, and then restarting oral administration of the nirogasistat or its pharmaceutically acceptable salt at a dose of 50 mg (free base equivalent dose) twice a day; (f) when the patient still develops Grade 3 hypokalemia after receiving maximum replacement therapy, suspending the administration of the nirogasistat or its pharmaceutically acceptable salt until the hypokalemia resolves to no higher than Grade 1 hypokalemia or baseline, and then restarting oral administration of the nirogasistat or its pharmaceutically acceptable salt at a dose of 50 mg (free base equivalent dose) twice a day; and (g) When the patient develops alanine aminotransferase (ALT) or aspartate aminotransferase (AST) of 3 to 5 times the upper limit of normal (ULN), the administration of the nirogasistat or its pharmaceutically acceptable salt is suspended until the ALT, AST or both subside to no higher than 3 times the ULN or baseline, and then the oral administration of the nirogasistat or its pharmaceutically acceptable salt is resumed at a dose of 50 mg (free base equivalent dose) twice a day.

43. The method of claim 42, wherein the patient is concurrently administered BCMA therapy.

44. The method of claim 42 or 43, further comprising one or more of the following: (h) when the patient develops ALT or AST greater than 5 times ULN, permanently discontinue the treatment with nirogasistat or a pharmaceutically acceptable salt thereof; (i) when the patient develops anaphylactic shock or other severe hypersensitivity reactions, permanently terminate the treatment with nirogasistat or its pharmaceutically acceptable salt; and (j) for another serious adverse reaction or in the case of a life-threatening adverse reaction, withhold the administration of the nirogasistat or its pharmaceutically acceptable salt until the adverse reaction resolves to no higher than Grade 1 adverse reaction or baseline, and then, after careful consideration of the potential benefit and the possibility of recurrence of the adverse reaction, (A) restart oral administration of the nirogasistat or its pharmaceutically acceptable salt at a dose of 50 mg (free base equivalent dose) twice daily, and (B) permanently discontinue treatment with the nirogasistat or its pharmaceutically acceptable salt upon recurrence of a severe or life-threatening adverse reaction at a dose of 50 mg (free base equivalent dose) twice daily.

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